Ccr2 receptor antagonists

ABSTRACT

The present invention relates to novel antagonists for CCR2 (CC chemokine receptor 2) and their use for providing medicaments for treating conditions and diseases, especially pulmonary diseases like asthma and COPD.

FIELD OF INVENTION

The present invention relates to novel antagonists for CCR2 (CCchemokine receptor 2) and their use for providing medicaments fortreating conditions and diseases where activation of CCR2 plays acausative role, especially pulmonary diseases like asthma and COPD,neurologic disease, especially of pain diseases, immune relateddiseases, especially diabetes mellitus including diabetes nephropathy,and cardiovascular diseases, especially atherosclerotic disease.

BACKGROUND OF THE INVENTION

The chemokines are a family of small, proinflammatory cytokines, withpotent chemotactic activities. Chemokines are chemotactic cytokines thatare released by a wide variety of cells to attract various cells, suchas monocytes, macrophages, T cells, eosinophils, basophils andneutrophils to sites of inflammation.

Chemokine receptors, such as CCR2 or CCR5 have been implicated as beingimportant mediators of inflammatory and immunoregulatory disorders anddiseases as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis. Accordingly, agents which modulate chemokinereceptors such as the CCR2 and CCR5 receptor would be useful in suchdisorders and diseases.

In particular it is widely accepted that numerous conditions anddiseases involve inflammatory processes. Such inflammations arecritically triggered and/or promoted by the activity of macrophages,which are formed by differentiation out of monocytes. It has furtherbeen found that monocytes are characterized by, e.g., a high expressionof membrane-resident CCR2, whereas the CCR2 expression in macrophages islower. CCR2 is a critical regulator of monocytes trafficking, which canbe described as the movement of the monocytes towards an inflammationalong a gradient of monocyte chemoattractant proteins (MCP-1, MCP-2,MCP-3, MCP-4).

Therefore, in order to reduce macrophage-induced inflammation, it wouldbe desirable to block the monocyte CCR2 by an antagonist, so that themonocytes can be less triggered to move towards an inflammation area forconversion into macrophages.

Based on the aforesaid there is a need for providing effectiveantagonists for CCR2, which are pharmacologically acceptable.

DESCRIPTION OF THE INVENTION

It has now been found that such effective CCR2 inhibitors can beprovided by compounds according to general formula (I),

wherein A is a group selected from among —NH-L₁-R₇, —NCH₃-L₁-R₇,—O-L₁-R₇, and the structure (II)

wherein L₁ is a linker selected from a bond or a group selected fromamong —C₁-C₂-alkylene, and —C₁-C₂-alkenylene which optionally comprisesone or more groups selected from —O—, —C(O)—, and —NH— in the chain andwhich is optionally substituted by a group selected from among —OH,—NH₂, —C₁-C₃-alkyl, O—C₁-C₆-alkyl, and —CN,wherein R₇ is a ring selected from among —C₃-C₈-cycloalkyl,—C₃-C₈-heterocyclyl, —C₅-C₁₀-aryl, and —C₅-C₁₀-heteroaryl,wherein the ring R₇ is optionally substituted with one or more groupsselected from among —CF₃, —C₁-C₆-alkyl, —O—CF₃, —CN, —O—C₁-C₆-alkyl,—C₁-C₆-alkenyl, and —C₁-C₆-alkynyl, and -halogen,or wherein the ring R₇ is optionally substituted with one or more groupsselected from among —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl,—C₃-C₈-heterocyclyl, optionally being substituted by one or more groupsselected from among —OH, —NH₂, —C₁-C₄-alkyl, —O—C₁-C₆-alkyl, —CN, —CF₃,—OCF₃, halogen, and ═O,or wherein the ring R₇ is optionally further bi-valently substituted ontwo neighbouring ring atoms, such that an annellated ring is formed byone or more groups selected from among —C₁-C₆-alkylene,—C₂-C₆-alkenylene and —C₄-C₆-alkynylene, in which one or two carboncenters may optionally be replaced by 1 or 2 hetero atoms selected fromN, O and S, the bivalent group being optionally substituted by one ormore groups selected from —OH, —NH₂, —C₁-C₃-alkyl, —O—C₁-C₆-alkyl, —CN,—CF₃, —OCF₃, halogen, and ═O;wherein R₆ is selected from among —H, -halogen, —CN, —O—C₁-C₄-alkyl,—C₁-C₄-alkyl, —CH═CH₂, —C≡CH, —CF₃, —OCF₃, —OCF₂H, and —OCFH₂;wherein R₂ is selected from among —H, -halogen, —CN, —O—C₁-C₄-alkyl,—C₁-C₄-alkyl, —CH═CH₂, —C≡CH, -cyclopropyl, —CF₃, —OCF₃, —OCF₂H, and—OCFH₂;wherein R₃ is selected from among —H, -methyl, -ethyl, -propyl,-i-propyl, -cyclopropyl, —OCH₃, —OH, and —CN;wherein Z is C or N;wherein R₁ is selected from among —H, —C₁-C₄-alkyl, —OH, —O—C₁-C₄-alkyl,-halogen, —CN, —CF₃, and —OCF₃;wherein n is 1, 2 or 3;wherein R₄ and R₅ are independently selected from among an electronpair, —H, and a group selected from among —C₁-C₆-alkyl, —NH₂,—C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl, —C₅-C₁₀-aryl,—C₅-C₁₀-heteroaryl, and —C(O)—N(R₈,R_(8′)), with R₈ and R_(8′)independently being selected from among —H, and —C₁-C₆-alkyl,and wherein R₄ and R₅ if different from an electron pair or —H areoptionally independently substituted with one or more groups selectedfrom among -halogen, —OH, —CF₃, —CN, —C₁-C₆-alkyl, —O—C₁-C₆-alkyl,—O—C₃-C₈-cycloalkyl, —O—C₃-C₈-heterocyclyl, —O—C₅-C₁₀-aryl,—O—C₅-C₁₀-heteroaryl, —C₀-C₆-alkylene-CN, —C₀-C₄-alkylene-O—C₁-C₄-alkyl,—C₀-C₄-alkylene-O—C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-O—C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-O—C₅-C₁₀-aryl,—C₀-C₄-alkylene-O—C₅-C₁₀-heteroaryl,—C₀-C₄-alkylene-Q—C₀-C₄-alkyl-N(R₉,R_(9′)),—C₀-C₄-alkylene-N(R₁₀)-Q-C₁-C₄-alkyl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₃-C₈-heterocyclyl,—C₀-C₄-alkylene-N(R₁₀)-Q—C₅-C₁₀-aryl,—C₀-C₄-alkylene-N(R₁₀)-Q—C₅-C₁₀-heteroaryl,—C₀-C₄-alkylene-Q-N(R₁₁,R_(11′)),—C₀-C₄-alkylene-N(R₁₂)-Q-N(R₁₃,R_(13′)), —C₀-C₄-alkylene-R₁₄,—C₀-C₄-alkylene-Q-C₁-C₆-alkyl, —C₀-C₄-alkylene-Q-C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-Q-C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-Q—C₅-C₁₀-aryl,—C₀-C₄-alkylene-Q—C₅-C₁₀-heteroaryl, —C₀-C₄-alkylene-O-Q-N(R₁₅,R_(15′)),and —C₀-C₄-alkylene-N(R₁₆)-Q-O—(R₁₇),wherein Q is selected from among —C(O)—, and —SO₂—,wherein R₁₂, R₁₆, are independently selected from among —H,—C₁-C₆-alkyl, and —C₃-C₆-cycloalkyl,wherein R₉, R_(9′), R₁₀, R₁₁, R_(11′), R₁₃, R_(13′), R₁₅, R_(15′), areindependently selected from among —H, —C₁-C₆-alkyl, and—C₃-C₆-cycloalkyl, or wherein R₉ and R_(9′), R₁₁ and R_(11′), R₁₃ andR_(13′), R₁₅ and R_(15′) together form a —C₂-C₆-alkylene group,wherein R₁₄ and R₁₇ are independently selected from among —H,—C₁-C₆-alkyl, —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl, and—C₃-C₈-heterocyclyl, wherein said —C₃-C₈-heterocyclyl optionallycomprises nitrogen and/or —SO₂— in the ring,and wherein R₁₄ and R₁₇ are optionally substituted with one or moregroups selected from among —OH, —OCH₃, —CF₃, —OCF₃, —CN, -halogen,—C₁-C₄-alkyl, ═O, and —SO₂—C₁-C₄-alkyl, or wherein R₄ and/or R₅ areindependently selected from among an electron pair, —H, and a group ofthe structure -L₂-R₁₈,wherein L₂ is selected from among —NH— and —N(C₁-C₄-alkyl)-,wherein R₁₈ is selected from among —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl,—C₃-C₈-cycloalkyl, and —C₃-C₈-heterocyclyl,wherein R₁₈ is optionally substituted by one or more groups selectedfrom among halogen, —CF₃, —OCF₃, —CN, —OH, —O—C₁-C₄-alkyl, —C₁-C₆-alkyl,—NH—C(O)—C₁-C₆-alkyl, —N(C₁-C₄-alkyl)-C(O)—C₁-C₆-alkyl,—C(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, —NH—S(O)₂—C₁-C₆-alkyl,—N(C₁-C₄-alkyl)-S(O)₂—C₁-C₆-alkyl, and —C(O)—O—C₁-C₆-alkyl, and whereinR₄, R₅ and R₁₈ are optionally further substituted byspiro-C₃-C₈-cycloalkyl or spiro-C₃-C₈-heterocyclyl such that togetherwith R₄, R₅ and/or R₁₈ a spirocycle is formed, wherein saidspiro-C₃-C₈-heterocyclyl optionally comprises one or more groupsselected from among nitrogen, —C(O)—, —SO₂—, and —N(SO₂—C₁-C₄-alkyl)- inthe ring, or wherein R₄, R₅ and R₁₈ are optionally further bi-valentlysubstituted by one or more spirocyclic or annellated ring forming groupsselected from among —C₁-C₆-alkylene, —C₂-C₆-alkenylene, and—C₄-C₆-alkynylene, in which one ore two carbon centers may optionally bereplaced by one or two hetero atoms selected from among N, O and S andwhich may optionally be substituted by one or more groups on one ringatom or on two neighbouring ring atoms selected from among —OH, —NH₂,—C₁-C₃-alkyl, O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, and halogen;as well as in form of their acid addition salts with pharmacologicallyacceptable acids.

Preferred compounds of the invention are compounds according to formula(I)

wherein A is a group selected from among —NH-L₁-R₇, —NCH₃-L₁-R₇,—O-L₁-R₇, and the structure (II)

wherein L₁ is a linker selected from a bond or a group selected fromamong —C₁-C₂-alkylene, and —C₁-C₂-alkenylene which optionally comprisesone or more groups selected from —O—, —C(O)—, and —NH— in the chain andwhich is optionally substituted by a group selected from among —OH,—NH₂, —C₁-C₃-alkyl, O—C₁-C₆-alkyl, and —CN,wherein R₇ is a ring selected from among —C₃-C₈-cycloalkyl,—C₃-C₈-heterocyclyl, —C₅-C₁₀-aryl, and —C₅-C₁₀-heteroaryl,wherein the ring R₇ is optionally substituted with one or more groupsselected from among —CF₃, —C₁-C₆-alkyl, —O—CF₃, —CN, —O—C₁-C₆-alkyl,—C₁-C₆-alkenyl, and —C₁-C₆-alkynyl, and -halogen,or wherein the ring R₇ is optionally substituted with one or more groupsselected from among —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl,—C₃-C₈-heterocyclyl, optionally being substituted by one or more groupsselected from among —OH, —NH₂, —C₁-C₄-alkyl, —O—C₁-C₆-alkyl, —CN, —CF₃,—OCF₃, halogen, and ═O,or wherein the ring R₇ is optionally further bi-valently substituted ontwo neighbouring ring atoms, such that an annellated ring is formed byone or more groups selected from among —C₁-C₆-alkylene,—C₂-C₆-alkenylene and —C₄-C₆-alkynylene, in which one or two carboncenters may optionally be replaced by 1 or 2 hetero atoms selected fromN, O and S, the bivalent group being optionally substituted by one ormore groups selected from —OH, —NH₂, —C₁-C₃-alkyl, —O—C₁-C₆-alkyl, —CN,—CF₃, —OCF₃, halogen, and ═O;wherein R₆ is selected from among —H, -halogen, —CN, —O—C₁-C₄-alkyl,—C₁-C₄-alkyl, —CH═CH₂, —C≡CH, —CF₃, —OCF₃, —OCF₂H, and —OCFH₂;wherein R₂ is selected from among —H, -halogen, —CN, —O—C₁-C₄-alkyl,—C₁-C₄-alkyl, —CH═CH₂, —C≡CH, -cyclopropyl, —CF₃, —OCF₃, —OCF₂H, and—OCFH₂;wherein R₃ is selected from among —H, -methyl, -ethyl, -propyl,-1-propyl, -cyclopropyl, —OCH₃, —OH, and —CN;wherein Z is C or N;wherein R₁ is selected from among —H, —C₁-C₄-alkyl, —OH, —O—C₁-C₄-alkyl,-halogen, —CN, —CF₃, and —OCF₃;wherein n is 1, 2 or 3;wherein R₅ is selected from among an electron pair, —H, and a groupselected from among —C₁-C₆-alkyl, —NH₂, —C₃-C₈-cycloalkyl,—C₃-C₈-heterocyclyl, —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, and—C(O)—N(R₈,R_(8′)), with R₈ and R_(8′) independently being selected fromamong —H, and —C₁-C₆-alkyl,and wherein R₅ if different from an electron pair or —H are optionallyindependently substituted with one or more groups selected from among-halogen, —OH, —CF₃, —CN, —C₁-C₆-alkyl, —O—C₁-C₆-alkyl,—O—C₃-C₈-cycloalkyl, —O—C₃-C₈-heterocyclyl, —O—C₅-C₁₀-aryl,—O—C₅-C₁₀-heteroaryl, —C₀-C₆-alkylene-CN, —C₀-C₄-alkylene-O—C₁-C₄-alkyl,—C₀-C₄-alkylene-O—C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-O—C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-O—C₅-C₁₀-aryl,—C₀-C₄-alkylene-O—C₅-C₁₀-heteroaryl,—C₀-C₄-alkylene-Q—C₀-C₄-alkyl-N(R₉,R_(9′)),—C₀-C₄-alkylene-N(R₁₀)-Q-C₁-C₄-alkyl, —C₀-C₄-alkylene-N(R₁₀)-Q-C₃ _(—)C₈-cycloalkyl, —C₀-C₄-alkylene-N(R₁₀)-Q-C₃-C₈-heterocyclyl,C₀-C₄-alkylene-N(R₁₀)-Q—C₅-C₁₀-aryl,—C₀-C₄-alkylene-N(R₁₀)-Q—C₅-C₁₀-heteroaryl,—C₀-C₄-alkylene-Q-N(R₁₁,R_(11′)),—C₀-C₄-alkylene-N(R₁₂)-Q-N(R₁₃,R_(13′)), —C₀-C₄-alkylene-R₁₄,—C₀-C₄-alkylene-Q-C₁-C₆-alkyl, —C₀-C₄-alkylene-Q-C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-Q-C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-Q—C₅-C₁₀-aryl,—C₀-C₄-alkylene-Q—C₅-C₁₀-heteroaryl, —C₀-C₄-alkylene-O-Q-N(R₁₅,R_(15′)),and —C₀-C₄-alkylene-N(R₁₆)-Q-O—(R₁₇),wherein Q is selected from among —C(O)—, and —SO₂—,wherein R₁₂, R₁₆, are independently selected from among —H,—C₁-C₆-alkyl, and —C₃-C₆-cycloalkyl,wherein R₉, R_(9′), R₁₀, R₁₁, R_(11′), R₁₃, R_(13′), R₁₅, R_(15′), areindependently selected from among —H, —C₁-C₆-alkyl, and—C₃-C₆-cycloalkyl,or wherein R₉ and R_(9′), R₁₁ and R_(11′), R₁₃ and R_(13′), R₁₅ andR_(15′) together form a —C₂-C₆-alkylene group,wherein R₁₄ and R₁₇ are independently selected from among —H,—C₁-C₆-alkyl, —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl, and—C₃-C₈-heterocyclyl, wherein said —C₃-C₈-heterocyclyl optionallycomprises nitrogen and/or —SO₂— in the ring,and wherein R₁₄ and R₁₇ are optionally substituted with one or moregroups selected from among —OH, —OCH₃, —CF₃, —OCF₃, —CN, -halogen,—C₁-C₄-alkyl, ═O, and —SO₂—C₁-C₄-alkyl, or wherein R₅ is selected fromamong an electron pair, —H, and a group of the structure -L₂-R₁₈,wherein L₂ is selected from among —NH— and —N(C₁-C₄-alkyl)-,wherein R₁₈ is selected from among —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl,—C₃-C₈-cycloalkyl, and —C₃-C₈-heterocyclyl,wherein R₁₈ is optionally substituted by one or more groups selectedfrom among halogen, —CF₃, —OCF₃, —CN, —OH, —O—C₁-C₄-alkyl, —C₁-C₆-alkyl,—NH—C(O)—C₁-C₆-alkyl, —N(C₁-C₄-alkyl)-C(O)—C₁-C₆-alkyl,—C(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, —NH—S(O)₂—C₁-C₆-alkyl,—N(C₁-C₄-alkyl)-S(O)₂—C₁-C₆-alkyl, and —C(O)—O—C₁-C₆-alkyl,and wherein R₄, R₅ and R₁₈ are optionally further substituted byspiro-C₃-C₈-cycloalkyl or spiro-C₃-C₈-heterocyclyl such that togetherwith R₄, R₅ and/or R₁₈ a spirocycle is formed,wherein said spiro-C₃-C₈-heterocyclyl optionally comprises one or moregroups selected from among nitrogen, —C(O)—, —SO₂—, and—N(SO₂—C₁-C₄-alkyl)- in the ring,or wherein R₅ and R₁₈ are optionally further bi-valently substituted byone or more spirocyclic or annellated ring forming groups selected fromamong —C₁-C₆-alkylene, —C₂-C₆-alkenylene,and —C₄-C₆-alkynylene, in which one ore two carbon centers mayoptionally be replaced by one or two hetero atoms selected from among N,O and S and which may optionally be substituted by one or more groups onone ring atom or on two neighbouring ring atoms selected from among —OH,—NH₂, —C₁-C₃-alkyl, O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, and halogen;wherein R₄ is selected from among —H, —C₁-C₃-alkyl, —OH, —CF₃, —OCF₃,and halogen, more preferred from among —H, and —C₁-C₃-alkyl, mostpreferred wherein R₄ denotes —H; as well as in form of their acidaddition salts with pharmacologically acceptable acids.

Preferred compounds of formula (I) according to the invention arecompounds,

wherein A is a group selected from among —NH-L₁-R₇, —O-L₁-R₇, and thestructure (II)

wherein L₁ is a linker selected from a bond or a group selected fromamong —C₁-C₂-alkylene,wherein R₇ is a ring selected from among —C₃-C₈-cycloalkyl,—C₃-C₈-heterocyclyl, and —C₅-C₁₀-aryl, wherein the ring R₇ is optionallysubstituted with one or more groups selected from among —CF₃,—C₁-C₆-alkyl, and —O—CF₃,or wherein the ring R₇ is optionally substituted with one or more groupsselected from among —C₅-C₁₀-aryl, optionally being substituted by one ormore groups selected from among —C₁-C₄-alkyl, and —OCF₃;wherein R₆ denotes —CF₃;wherein R₂ is selected from among —H, —C₁-C₄-alkyl, and —CF₃;wherein R₃ is selected from among —H, —OCH₃, and —OH;wherein Z denotes C;wherein R₁ denotes —H;wherein n is 2;wherein R₄ denotes —H, and R₅ is a group selected from—C₃-C₈-heterocyclyl,and wherein R₅ is optionally substituted with one or more groupsselected from among —C₀-C₄-alkylene-N(R₁₀)-Q-C₁-C₄-alkyl,wherein Q is denotes —SO₂—, and wherein R₁₀, is selected from among —H,and —C₁-C₆-alkyl,or wherein R₄ denotes —H, and R₅ is selected from a group of thestructure -L₂-R₁₈,wherein L₂ denotes —NH— and wherein R₁₈ is selected from among—C₃-C₈-heterocyclyl,wherein R₁₈ is optionally substituted by one or more groups selectedfrom among —O—C₁-C₄-alkyl.

Preferred compounds of formula (I) according to the invention arecompounds,

wherein A is a group selected from among —NH-L₁-R₇, and the structure(II)

wherein L₁ is a linker selected from a bond or a group selected fromamong —C₁-C₂-alkylene,wherein R₇ is a ring selected from among —C₃-C₈-cycloalkyl,—C₃-C₈-heterocyclyl, and —C₅-C₁₀-aryl, wherein the ring R₇ is optionallysubstituted with one or more groups selected from among —CF₃,—C₁-C₆-alkyl, and —O—CF₃,or wherein the ring R₇ is optionally substituted with one or more groupsselected from among —C₅-C₁₀-aryl, optionally being substituted by one ormore groups selected from among —C₁-C₄-alkyl, and —OCF₃;wherein R₆ denotes —CF₃;wherein R₂ is selected from among —H, —C₁-C₄-alkyl, and —CF₃;wherein R₃ is selected from among —H, and —OCH₃;wherein Z denotes C;wherein R₁ denotes —H;wherein n is 2;wherein R₄ denotes —H, and R₅ is a group selected from—C₃-C₈-heterocyclyl,and wherein R₅ is optionally substituted with one or more groupsselected from among —C₀-C₄-alkylene-N(R₁₀)-Q-C₁-C₄-alkyl,wherein Q is denotes —SO₂—, and wherein R₁₀, is selected from among —H,and —C₁-C₃-alkyl,or wherein R₄ denotes —H, and R₅ is selected from a group of thestructure -L₂-R₁₈,wherein L₂ denotes —NH— and wherein R₁₈ is selected from among—C₃-C₈-heterocyclyl,wherein R₁₈ is optionally substituted by one or more groups selectedfrom among —O—CH₃.

Preferred compounds of formula (I) according to the invention arecompounds with R₂, R₃, R₄, R₅, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁,R_(11′)R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′)R₁₆, R₁₇, R₁₈, R₂₀, R_(20′),R₂₁, R_(21′), L₂, Z, Q, and n as herein before or below defined,

wherein A is —NH-L₁-R₇,and wherein L₁ is a bond or wherein L₁ denotes methylene,and wherein R₇ is a ring selected from among -cyclopropyl, -cyclobutyl,-cyclopentyl, -cyclohexyl, -cycloheptyl, -pyrrolidinyl, -piperidinyl,-azepanyl, -tetrahydrofuranyl, -tetrahydropyranyl, -oxepanyl, -phenyl,-pyridyl, and -furanyl,wherein the ring R₇ is optionally substituted with one or more groupsselected from among —F, —Cl, -methyl, -ethyl, -propyl, -1-propyl,-cyclopropyl, -t-butyl, —CF₃, —O—CF₃, —CN, —O-methyl, -furanyl and-phenyl, wherein said -phenyl is optionally independently substituted byone or more groups selected from among —C₁-C₄-alkyl, halogen, —OCH₃,—CF₃, and —OCF₃.

Preferred compounds of formula (I) according to the invention arecompounds with R₂, R₃, R₄, R₅, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁,R_(11′)R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′)R₁₆, R₁₇, R₁₈, R₂₀, R_(20′),R₂₁, R_(21′), L₂, Z, Q, and n as herein before or below defined,

wherein A is —NH-L₁-R₇,and wherein L₁ is a bond or wherein L₁ denotes methylene,and wherein R₇ is a ring selected from among -cyclohexyl,-tetrahydropyranyl, and -phenyl,wherein the ring R₇ is optionally substituted with one or more groupsselected from among -t-butyl, and -phenyl, wherein said -phenyl isoptionally independently substituted by one or more groups selected fromamong —C₁-C₄-alkyl, —CF₃, and —OCF₃.

Preferred compounds of formula (I) according to the invention arecompounds with R₂, R₃, R₄, R₅, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁,R_(11′)R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′)R₁₆, R₁₇, R₁₈, R₂₀, R_(20′),R₂₁, R_(21′), L₂, Z, Q, and n as herein before or below defined,

wherein A is —NH-L₁-R₇and wherein L₁ is a bond or wherein L₁ denotes methylene,and wherein R₇ is a ring selected from among —C₃-C₈-heterocyclyl, and—C₅-C₁₀-aryl,wherein the ring R₇ is optionally substituted with one or more groupsselected from among —O—CF₃, —C₁-C₆-alkyl,or wherein the ring R₇ is optionally substituted with one or more groupsselected from -phenyl, optionally being substituted by one or moregroups selected from —C₁-C₄-alkyl, and —OCF₃.

Preferred compounds of formula (I) according to the invention arecompounds with R₂, R₃, R₄, R₅, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁,R_(11′)R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′)R₁₆, R₁₇, R₁₈, R₂₀, R_(20′),R₂₁, R_(21′), L₂, Z, Q, and n as herein before or below defined,

wherein A denotes a group selected from among formula (III)

wherein R₁₉ denotes the ring —C₅-C₁₀-aryl, preferably wherein R₁₉denotes -phenyl, andwherein the ring R₁₉ is optionally substituted with one or more groupsselected from among —O—CF₃, and —C₁-C₆-alkyl, preferably by a groupselected from among —O—CF₃.

Preferred compounds of formula (I) according to the invention arecompounds with R₂, R₃, R₄, R₅, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁,R_(11′)R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′)R₁₆, R₁₇, R₁₈, R₂₀, R_(20′),R₂₁, R_(21′), L₂, Z, Q, and n as herein before or below defined,

wherein A is a group selected from among formula (IV) and (V)

wherein R₁₉ is selected from among —H, —O—CF₃, and —C₁-C₆-alkyl.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₃, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁,R_(11′)R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′)R₁₆, R₁₇, R₁₈, R₁₉, R₂₀,R_(20′), R₂₁, R_(21′), A, L₁, L₂, Z, Q, and n as herein before or belowdefined,

wherein R₂ is selected from among —H, —CF₃, and —CH₃, preferablyselected from —CH₃.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁,R_(11′)R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′)R₁₆, R₁₇, R₁₈, R₁₉, R₂₀,R_(20′), R₂₁, R_(21′), A, L₁, L₂, Z, Q, and n as herein before or belowdefined,

wherein R₃ is selected from among —H, —OCH₃, and -methyl, preferablyselected from —OCH₃.

Preferred compounds of formula (I) according to the invention arecompounds with R₂, R₃, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁,R_(11′)R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′)R₁₆, R₁₇, R₁₈, R₁₉, R₂₀,R_(20′), R₂₁, R_(21′), A, L₁, L₂, Z, Q, and n as herein before or belowdefined,

wherein R₁ is selected from among —H, and —CH₃, preferably wherein R₁denotes —H.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀, R₁₁,R_(11′)R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′)R₁₆, R₁₇, R₁₈, R₁₉, R₂₀,R_(20′), R₂₁, R_(21′), A, L₁, L₂, Z, Q, and n as herein before or belowdefined,

wherein R₄ denotes —H.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀,R₁₁, R_(11′)R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′)R₁₆, R₁₇, R₁₈, R₁₉, R₂₀,R_(20′), R₂₁, R_(21′), A, L₁, L₂, Z, and Q, as herein before or belowdefined,

wherein n is 2.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉, R_(9′), R₁₀,R₁₁, R_(11′)R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′)R₁₆, R₁₇, R₁₈, R₁₉, R₂₀,R_(20′), R₂₁, R_(21′), A, L₁, L₂, Z, Q, and n as herein before or belowdefined,

wherein Z denotes C.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₁₉, A, L₁, Q, and n as herein beforeor below defined,

wherein

Z denotes C, and

wherein R₄ denotes —H, and wherein R₅ denotes a group of the structure-L₂-R₁₈,wherein L₂ is a group selected from among —NH—, and —N(CH₃)—,wherein R₁₈ is —C₆-heterocyclyl comprising 1 hetero atom selected fromO,wherein R₁₈ is optionally substituted by —O—CH₃;or wherein R₄ denotes —H and R₅ denotes a group of the structure—N(R₂₀,R_(20′)),wherein R₂₀ and R_(20′) together form a —C₄-C₅-alkylene group such thata ring is formed,wherein such ring is optionally substituted with one or more groupsselected from among —OH, and —N(C₀-C₁-alkyl)-SO₂—CH₃;or wherein R₄ denotes —H, and wherein R₅ denotes a group of thestructure —N(R₂₁,R_(21′)),wherein R₂₁ and R_(21′) together form a —C₅-alkylene group such that aring is formed, in which one carbon center of the —C₅-alkylene group isreplaced by one hetero atom selected from O.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₁₉, A, L₁, Q, and n as herein beforeor below defined,

whereinZ denotes C, andwherein R₄ denotes —H, and wherein R₅ denotes a group of the structure-L₂-R₁₈,wherein L₂ is a group selected from among —NH—, and —N(CH₃)—,wherein R₁₈ is —C₆-heterocyclyl comprising 1 hetero atom selected fromO,wherein R₁₈ is optionally substituted by a group selected from among —F,and —O—CH₃;or wherein R₄ denotes —H and R₅ denotes a group of the structure—N(R₂₀,R_(20′)),wherein R₂₀ and R_(20′) together form a —C₄-C₅-alkylene group such thata ring is formed,wherein such ring is optionally substituted with one or more groupsselected from among —OH, and —N(C₀-C₁-alkyl)-SO₂—CH₃;or wherein R₄ denotes —H, and wherein R₅ denotes a group of thestructure —N(R₂₁,R_(21′)),wherein R₂₁ and R_(21′) together form a —C₅-alkylene group such that aring is formed, in which one carbon center of the —C₅-alkylene group isreplaced by one hetero atom selected from O.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₁₉, A, L₁, Q, and n as herein beforeor below defined,

whereinZ denotes C, andwherein R₄ denotes —H, and wherein R₅ denotes a group of the structure-L₂-R₁₈,wherein L₂ is a group selected from among —NH—, and —N(CH₃)—,wherein R₁₈ is —C₆-heterocyclyl comprising 1 hetero atom selected fromO,wherein R₁₈ is optionally substituted by —O—CH₃;or wherein R₄ denotes —H and R₅ denotes a group of the structure—N(R₂₀,R_(20′)),wherein R₂₀ and R_(20′) together form a —C₄-C₅-alkylene group such thata ring is formed,wherein such ring is optionally substituted with one or more groupsselected from among —OH, and —N(C₀-C₁-alkyl)-SO₂—CH₃

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₁₉, A, L₁, Q, and n as herein beforeor below defined,

whereinZ denotes C, andwherein R₄ denotes —H, and wherein R₅ denotes a group of the structure-L₂-R₁₈,wherein L₂ is a group selected from among —NH—,wherein R₁₈ is —C₆-heterocyclyl comprising 1 hetero atom selected fromO,wherein R₁₈ is optionally substituted by —O—CH₃;or wherein R₄ denotes —H and R₅ denotes a group of the structure—N(R₂₀,R_(20′)),wherein R₂₀ and R_(20′) together form a —C₄-C₅-alkylene group such thata ring is formed,wherein such ring is optionally substituted with one or more groupsselected from among —OH, and —N(C₀-C₁-alkyl)-SO₂—CH₃.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₁₉, A, L₁, Q, and n as herein beforeor below defined,

whereinZ denotes C, andwherein R₄ denotes —H, and wherein R₅ denotes a group of the structure-L₂-R₁₈,wherein L₂ is a group selected from among —NH—,wherein R₁₈ is —C₆-heterocyclyl comprising 1 hetero atom selected fromO,wherein R₁₈ is optionally substituted by —F;or wherein R₄ denotes —H and R₅ denotes a group of the structure—N(R₂₀,R_(20′)),wherein R₂₀ and R_(20′) together form a —C₄-C₅-alkylene group such thata ring is formed,wherein such ring is optionally substituted with one or more groupsselected from among —OH, and —N(C₀-C₁-alkyl)-SO₂—CH₃

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₁₉, A, L₁, Q, and n as herein beforeor below defined,

whereinZ denotes C, andwherein R₄ denotes —H, and wherein R₅ denotes a group of the structure-L₂-R₁₈,wherein L₂ is a group selected from among —NH—,wherein R₁₈ is —C₆-heterocyclyl comprising 1 hetero atom selected fromO,wherein R₁₈ is optionally substituted by —O—CH₃.

Preferred compounds of formula (I) according to the invention arecompounds with R₁, R₂, R₃, R₆, R₇, R₁₉, A, L₁, Q, and n as herein beforeor below defined,

whereinZ denotes C, andwherein R₄ denotes —H, and wherein R₅ denotes a group of the structure-L₂-R₁₈,wherein L₂ is a group selected from among —NH—,wherein R₁₈ is —C₆-heterocyclyl comprising 1 hetero atom selected fromO,wherein R₁₈ is optionally substituted by —F.

All of the above embodiments under formula (I) have to be understood tooptionally be present in form of their individual optical isomers,mixtures of their individual optical isomers, or racemates, as well asin form of their acid addition salts with pharmacologically acceptableacids, as well as in form of their solvates and/or hydrates.

It has now been found that such compounds as herein before or belowdefined could be used as a medicament.

It has been found that such compounds as herein before or below definedcould be used for making a medicament for the treatment of inflammatorydiseases. It has been found that such compounds as herein before orbelow defined could be used for making a medicament for the treatment ofinflammatory diseases, wherein the inflammatory diseases are selectedfrom inflammatory diseases of the respiratory tract. It has been foundthat such compounds as herein before or below defined could be used formaking a medicament for the treatment of inflammatory diseases, whereinthe inflammatory diseases are selected from chronic obstructivepulmonary disease, asthma, and cystic fibrosis. It has been found thatsuch compounds as herein before or below defined could be used formaking a medicament for the treatment of neurologic diseases, preferablyfor the treatment of pain diseases especially for the treatment ofinflammatory and neuropathic pain disease, especially for the treatmentof chronic pain. It has been found that such compounds as herein beforeor below defined could be used for making a medicament for the treatmentof immune related diseases, preferably for the treatment of diabetesmellitus. It has been found that such compounds as herein before orbelow defined could be used for making a medicament for the treatment ofcardiovascular diseases, preferably for the treatment of peripheralatherosclerotic disease. It has been found that such compounds as hereinbefore or below defined could be used for making a medicament for thetreatment of diabetic nephropathy.

Present invention encloses compounds as herein before or below definedas medicaments. Present invention encloses compounds as herein before orbelow defined as medicaments for the treatment of inflammatory diseases.Present invention encloses compounds as herein before or below definedas medicaments for the treatment of inflammatory diseases, wherein theinflammatory diseases are selected from inflammatory diseases of therespiratory tract. Present invention encloses compounds as herein beforeor below defined as medicaments for the treatment of inflammatorydiseases, wherein the inflammatory diseases are selected from chronicobstructive pulmonary disease, asthma, and cystic fibrosis. Presentinvention encloses compounds as herein before or below defined asmedicaments for the treatment ofneurologic diseases, preferably for thetreatment of pain diseases especially for the treatment of inflammatoryand neuropathic pain disease, especially for the treatment of chronicpain. Present invention encloses compounds as herein before or belowdefined as medicaments for the treatment of immune related diseases,preferably for the treatment of diabetes mellitus. Present inventionencloses compounds as herein before or below defined as medicaments forthe treatment of cardiovascular diseases, preferably for the treatmentof peripheral atherosclerotic disease. Present invention enclosescompounds as herein before or below defined as medicaments for thetreatment of diabetic nephropathy.

It has been found that such compounds as herein before or below definedcould be used for the treatment of inflammatory diseases. It has beenfound that such compounds as herein before or below defined could beused for the treatment of inflammatory diseases, wherein theinflammatory diseases are selected from inflammatory diseases of therespiratory tract. It has been found that such compounds as hereinbefore or below defined could be used for the treatment of inflammatorydiseases, wherein the inflammatory diseases are selected from chronicobstructive pulmonary disease, asthma, and cystic fibrosis. It has beenfound that such compounds as herein before or below defined could beused for the treatment of neurologic diseases, preferably for thetreatment of pain diseases especially for the treatment of inflammatoryand neuropathic pain disease, especially for the treatment of chronicpain. It has been found that such compounds as herein before or belowdefined could be used for the treatment of immune related diseases,preferably for the treatment of diabetes mellitus. It has been foundthat such compounds as herein before or below defined could be used forthe treatment of cardiovascular diseases, preferably for the treatmentof peripheral atherosclerotic disease. It has been found that suchcompounds as herein before or below defined could be used for thetreatment of diabetic nephropathy.

DEFINITIONS

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, —C₁-C₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms. In general,for groups comprising two or more subgroups, the last named subgroup isthe radical attachment point, for example, the substituent“aryl-C₁-C₃-alkyl-” means an aryl group which is bound to aC₁-C₃-alkyl-group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

In case a compound of the present invention is depicted in form of achemical name and as a formula in case of any discrepancy the formulashall prevail. An asterisk is may be used in sub-formulas to indicatethe bond which is connected to the core molecule as defined.

For example, the term “3-carboxypropyl-group” represents the followingsubstituent:

wherein the carboxy group is attached to the third carbon atom of thepropyl group. The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or“cyclopropylmethyl-” group represent the following groups:

The asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

Many of the followings terms may be used repeatedly in the definition ofa formula or group and in each case have one of the meanings givenabove, independently of one another.

Unless otherwise stated, all the substituents are independent of oneanother. If for example there might be a plurality of C₁-C₆-alkyl groupsas substituents in one group, in the case of three substituentsC₁-C₆-alkyl, one may represent methyl, one n-propyl and one tert-butyl.

Within the scope of this application, in the definition of possiblesubstituents, these may also be represented in the form of a structuralformula. An asterisk (*) in the structural formula of the substituent isto be understood as being the linking point to the rest of the molecule.Moreover, the atom of the substituent which follows the linking point isreferred to as the atom in position number 1. Thus, for example, thegroups N-piperidinyl (Piperidin-A), 4-piperidinyl (Piperidin-B), 2-tolyl(Tolyl-C), 3-tolyl (Tolyl-D), and 4-tolyl (Tolyl-E) are shown asfollows:

If there is no asterisk (*) in the structural formula of thesubstituent, each hydrogen atom may be removed from the substituent andthe valency thus freed may act as a binding site to the rest of amolecule. Thus, for example, (Tolyl-F) may represent 2-tolyl, 3-tolyl,4-tolyl, and benzyl

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valence isnot exceeded, and that the substitution results in a stable compound.

By the term “optionally substituted” is meant within the scope of theinvention the above-mentioned group, optionally substituted by alower-molecular group. Examples of lower-molecular groups regarded aschemically meaningful are groups consisting of 1-200 atoms. Preferablysuch groups have no negative effect on the pharmacological efficacy ofthe compounds. For example the groups may comprise:

-   -   Straight-chain or branched carbon chains, optionally interrupted        by heteroatoms, optionally substituted by rings, heteroatoms or        other common functional groups.    -   Aromatic or non-aromatic ring systems consisting of carbon atoms        and optionally heteroatoms, which may in turn be substituted by        functional groups.    -   A number of aromatic or non-aromatic ring systems consisting of        carbon atoms and optionally heteroatoms which may be linked by        one or more carbon chains, optionally interrupted by        heteroatoms, optionally substituted by heteroatoms or other        common functional groups.

By the term “branched or unbranched, saturated or unsaturatedC₁-C₆-carbon chain” it is meant a chain of carbon atoms, which isconstituted by 1 to 6 carbon atoms arranged in a row and which canoptionally further comprise branches or one or more hetero atomsselected from N, O or S. Said carbon chain can be saturated orunsaturated by comprising double or triple bonds.

If the carbon chain is to be substituted by a group which together withone or two carbon atoms of an alkylene chain forms a carbocyclic ringwith 3, 5 or 6 carbon atoms, this includes the following examples of therings:

The term “C₁-C_(n)-alkyl”, wherein n is an integer from 2 to n, eitheralone or in combination with another radical denotes an acyclic,saturated, branched or linear hydrocarbon radical with 1 to n C atoms.For example the term C₁-C₈-alkyl embraces the radicals H₃C—, H₃C—CH₂—,H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—,H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

By the term “C₁-C₆-alkyl” (including those which are part of othergroups) are meant branched and unbranched alkyl groups with 1 to 6carbon atoms and by the term “C₁-C₄-alkyl” are meant branched andunbranched alkyl groups with 1 to 4 carbon atoms. Alkyl groups with 1 to4 carbon atoms are preferred. By the term “C₁-C₃-alkyl” are meantbranched and unbranched alkyl groups with 1 to 3 carbon atoms and by theterm “C₂-C₄-alkyl” are meant branched and unbranched alkyl groups with 2to 4 carbon atoms. Examples for alkyl groups with 1-6 carbon atomsinclude: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl or hexyl.Optionally the abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc.may also be used for the above-mentioned groups. Unless statedotherwise, the definitions propyl, butyl, pentyl and hexyl include allthe possible isomeric forms of the groups in question. Thus, forexample, propyl includes n-propyl and iso-propyl, butyl includesiso-butyl, sec-butyl and tert-butyl etc.

The term “C₁-C_(n)-alkylene” wherein n is an integer 2 to n, eitheralone or in combination with another radical, denotes an acyclic,straight or branched chain divalent alkyl radical containing from 1 to ncarbon atoms. For example the term C₁-C₄-alkylene includes —CH₂—,—CH₂—CH₂—, —CH(CH₃)—, —CH₂—CH₂—CH₂—, —C(CH₃)₂—, —CH(CH₂CH₃)—,—CH(CH₃)—CH₂—, —CH₂—CH(CH₃)—, —CH₂—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH(CH₃)—,—CH(CH₃)—CH₂—CH₂—, —CH₂—CH(CH₃)—CH₂—, —CH₂—C(CH₃)₂—, —C(CH₃)₂—CH₂—,—CH(CH₃)—CH(CH₃)—, —CH₂—CH(CH₂CH₃)—, —CH(CH₂CH₃)—CH₂—, —CH(CH₂CH₂CH₃)—,—CH(CH(CH₃))₂— and —C(CH₃)(CH₂CH₃)—.

By the term “C₁-C₈-alkylene” (including those which are part of othergroups) are meant branched and unbranched alkylene groups with 1 to 8carbon atoms. By the term “C₂-C₈-alkylene” are meant branched andunbranched alkylene groups with 2 to 8 carbon atoms. By the term“C₂-C₆-alkylene” are meant branched and unbranched alkylene groups with2 to 6 carbon atoms. By the term “C₁-C₄-alkylene” are meant branched andunbranched alkylene groups with 1 to 4 carbon atoms. By the term“C₁-C₂-alkylene” are meant branched and unbranched alkylene groups with1 to 2 carbon atoms. By the term “C₀-C₄-alkylene” are meant branched andunbranched alkylene groups with 0 to 4 carbon atoms, thus also a singlebond is encompassed. By the term “C₁-C₃-alkylene” are meant branched andunbranched alkylene groups with 1 to 3 carbon atoms. Examples forC₁-C₈-alkylene include: methylene, ethylene, propylene,1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene,1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene,2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene,hexylene, heptylene or octylene. Unless stated otherwise, thedefinitions propylene, butylene, pentylene, hexylene, heptylene andoctylene include all the possible isomeric forms of the groups inquestion with the same number of carbons. Thus, for example, propyl alsoincludes 1-methylethylene and butylene includes 1-methylpropylene,1,1-dimethylethylene, 1,2-dimethylethylene.

A —C₁-alkylene group, which is linked to a structure on two neighbouringring atoms such that an annellated ring is formed, results to aC₃-carbocycle. A —C₂-alkylene group, which is linked to a structure ontwo neighbouring ring atoms such that an annellated ring is formed,results to a C₄-carbocycle. A —C₃-alkylene group, which is linked to astructure on two neighbouring ring atoms such that an annellated ring isformed, results to a C₅-carbocycle. A —C₄-alkylene group, which islinked to a structure on two neighbouring ring atoms such that anannellated ring is formed, results to a C₆-carbocycle. A —C₅-alkylenegroup, which is linked to a structure on two neighbouring ring atomssuch that an annellated ring is formed, results to a C₇-carbocycle. A—C₆-alkylene group, which is linked to a structure on two neighbouringring atoms such that an annellated ring is formed, results to aC₈-carbocycle.

In the definition of possible substituents, which are linked to suchC₁-C₆₋alkylene groups forming a C₃-C₈-carbocycle, it is to be understoodthat any of the atoms of the resulting C₃-C₈-carbocycles could be thelinking point for such a substituent.

If the carbon chain is to be substituted by a group which together withone or two carbon atoms of the alkylene chain forms a carbocyclic ringwith 3, 5 or 6 carbon atoms, this includes the following examples of therings:

The term “C₂-C_(n)-alkenyl”, is used for a group as defined in thedefinition for “C₁-C_(n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond.

By the term “C₂-C₆-alkenyl” (including those which are part of othergroups) are meant branched and unbranched alkenyl groups with 2 to 6carbon atoms and by the term “C₂-C₄-alkenyl” are meant branched andunbranched alkenyl groups with 2 to 4 carbon atoms, provided that theyhave at least one double bond. Alkenyl groups with 2 to 4 carbon atomsare preferred. Examples for C₂-C₆-alkenyls include: ethenyl or vinyl,propenyl, butenyl, pentenyl, or hexenyl. Unless stated otherwise, thedefinitions propenyl, butenyl, pentenyl and hexenyl include all thepossible isomeric forms of the groups in question. Thus, for example,propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1-, 2- and3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl etc.

By the term “methenylene” is meant a group with 1 carbon atom, providedthat it is linked by a single bond as well as on the other side by adouble bond. The asterisks (*) in the structural formula is to beunderstood as being the linking points to the rest of the molecule,whereas the valency of the rest of the molecule be freed thus a singleand a double bond can be formed by replacement of further hydrogens atthe binding site if applicable:

The term “C₂-C_(n)-alkenylene” is used for a group as defined in thedefinition for “C₁-C_(n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond.

By the term “C₂-C₈-alkenylene” (including those which are part of othergroups) are meant branched and unbranched alkenylene groups with 2 to 8carbon atoms and by the term “C₂-C₆-alkenylene” are meant branched andunbranched alkenylene groups with 2 to 6 carbon atoms. By the term“C₁-C₂-alkenylene” are meant alkenylene groups with 1 to 2 carbon atoms,provided that they have at least one double bond, whereas by the term“C₁-alkenylene” is meant “methenylene”. Examples for C₂-C₈-alkenylenesinclude: ethenylene, propenylene, 1-methylethenylene, butenylene,1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene,pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene,1,2-dimethylpropenylene, 1,3-dimethylpropenylene, hexenylene,heptenylene or octenylene. Unless stated otherwise, the definitionspropenylene, butenylene, pentenylene and hexenylene include all thepossible isomeric forms of the groups in question with the same numberof carbons. Thus, for example, propenyl also includes 1-methylethenyleneand butenylene includes 1-methylpropenylene, 1,1-dimethylethenylene,1,2-dimethylethenylene.

A —C₃-alkenylene group, which is linked to a structure on twoneighbouring ring atoms such that an annellated ring is formed, resultsto a C₅-carbocycle. A —C₄-alkenylene group, which is linked to astructure on two neighbouring ring atoms such that an annellated ring isformed, results to a C₆-carbocycle. A —C₅-alkenylene group, which islinked to a structure on two neighbouring ring atoms such that anannellated ring is formed, results to a C₇-carbocycle. A —C₆-alkenylenegroup, which is linked to a structure on two neighbouring ring atomssuch that an annellated ring is formed, results to a C₅-carbocycle.

In the definition of possible substituents, which are linked to suchC₃-C₆₋alkenylene groups forming a C₅-C₅-carbocycle, it is to beunderstood that any of the atoms of the resulting C₅-C₅-carbocyclescould be the linking point for such a substituent.

The term “C₂-C_(n)-alkynyl”, is used for a group as defined in thedefinition for “C₁-C_(n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond.

By the term “C₂-C₆-alkynyl” (including those which are part of othergroups) are meant branched and unbranched alkynyl groups with 2 to 6carbon atoms and by the term “C₂-C₄-alkynyl” are meant branched andunbranched alkynyl groups with 2 to 4 carbon atoms, provided that theyhave at least one triple bond. Examples for C₂-C₆-alkynyls include:ethynyl, propynyl, butynyl, pentynyl or hexynyl. Unless statedotherwise, the definitions propynyl, butynyl, pentynyl and hexynylinclude all the possible isomeric forms of the groups in question. Thusfor example propynyl includes 1-propynyl and 2-propynyl, butynylincludes 1-, 2-, and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyletc.

The term “C₂-C_(n)-alkynylene” is used for a group as defined in thedefinition for “C₁-C_(n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond.

By the term “C₂-C₈-alkynylene” (including those which are part of othergroups) are meant branched and unbranched alkynylene groups with 2 to 8carbon atoms and by the term “C₂-C₆-alkynylene” are meant branched andunbranched alkynylene groups with 2 to 6 carbon atoms. Examples ofC₂-C₈-alkynylenes include: ethynylene, propynylene, 1-methylethynylene,butynylene, 1-methylpropynylene, 1,1-dimethylethynylene,1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene,2,2-dimethylpropynylene, 1,2-dimethylpropynylene,1,3-dimethylpropynylene, hexynylene, heptynylene or octynylene. Unlessstated otherwise, the definitions propynylene, butynylene, pentynyleneand hexynylene include all the possible isomeric forms of the groups inquestion with the same number of carbons. Thus for example propynyl alsoincludes 1-methylethynylene and butynylene includes 1-methylpropynylene,1,1-dimethylethynylene, 1,2-dimethylethynylene.

The term “carbocyclyl” as used either alone or in combination withanother radical, means a mono- bi- or tricyclic ring structureconsisting of 3 to 14 carbon atoms. The term “carbocycle” refers tofully saturated and aromatic ring systems and partially saturated ringsystems. The term “carbocycle” encompasses fused, bridged andspirocyclic systems:

By the term “ring” are meant carbocycles, which can be saturated,unsaturated or aromatic and which optionally can comprise one or morehetero atoms selected from N, O or S.

The term “heterocyclyl” means a saturated or unsaturated mono- orpolycyclic-ring systems including aromatic ring system containing one ormore heteroatoms selected from N, O or S(O)_(r), wherein r=0, 1 or 2,consisting of 3 to 14 ring atoms wherein none of the heteroatoms is partof the aromatic ring. The term “heterocycle” is intended to include allthe possible isomeric forms.

Thus, the term “heterocyclyl” includes the following exemplarystructures which are not depicted as radicals as each form may beattached through a covalent bond to any atom so long as appropriatevalences are maintained:

By the term “—C₃-C₈-heterocyclyl” are meant three-, four-, five-, six-,seven-, or eight-membered, saturated or unsaturated heterocyclic ringswhich may contain one, two, or three heteroatoms, selected from amongoxygen, sulfur, and nitrogen, whereas carbon atoms be replaced by suchheteroatoms. The ring may be linked to the molecule through a carbonatom or through a nitrogen atom, if there is one. By the term“—C₅-C₈-heterocyclyl” are meant five-, six-, seven-, or eight-membered,saturated or unsaturated heterocyclic rings which may contain one, two,or three heteroatoms, selected from among oxygen, sulfur, and nitrogen,while the ring may be linked to the molecule through a carbon atom orthrough a nitrogen atom, if there is one.

Examples for C₅-heterocyclyl include:

Examples for C₆-heterocyclyl include:

Examples for C₇-heterocyclyl include:

Unless otherwise mentioned, a heterocyclic ring (or “heterocycle”) maybe provided with a keto group. Examples include:

The term “C₃-C_(n)-cycloalkyl”, wherein n is an integer from 3 to n,either alone or in combination with another radical denotes a cyclic,saturated, unbranched hydrocarbon radical with 3 to n C atoms. Forexample the term C₃-C₇-cycloalkyl includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

By the term “C₃-C₈-cycloalkyl” (including those which are part of othergroups) are meant cyclic alkyl groups with 3 to 8 carbon atoms.Likewise, by the term “C₃-C₆-cycloalkyl” are meant cyclic alkyl groupswith 3 to 6 carbon atoms. Examples of C₃-C₈-cycloalkyls include:cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl. Unless otherwise stated, the cyclic alkyl groups may besubstituted by one or more groups selected from among methyl, ethyl,isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine, and iodine.

The term “C₃-C_(n)-cycloalkenyl”, wherein n is an integer from 3 to n,either alone or in combination with another radical, denotes an cyclic,unsaturated but nonaromatic, unbranched hydrocarbon radical with 3 to nC atoms, at least two of which are bonded to each other by a doublebond. For example the term C₃-C₇-cycloalkenyl includes cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl,cyclohexadienyl, cycloheptenyl cycloheptadienyl and cycloheptatrienyl.

By the term “aryl” (including those which are part of other groups) aremeant aromatic ring systems. By the term “C₅-C₁₀-aryl” (including thosewhich are part of other groups) are meant aromatic ring systems with 5to 10 carbon atoms. Preferred are “C₆-C₁₀-aryl” groups whereas aromaticrings are meant with 6 to 10 carbon atoms. Examples include: phenyl ornaphthyl. Also preferred are “C₅-C₆-aryl” groups whereas aromatic ringsare meant with 5 to 6 carbon atoms Unless otherwise stated, the aromaticring systems may be substituted by one or more groups selected fromamong methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine,chlorine, bromine and iodine.

The term “heteroaryl” means a mono- or polycyclic-ring systemscontaining one or more heteroatoms selected from N, O or S(O)_(r),wherein r=0, 1 or 2, consisting of 5 to 14 ring atoms wherein at leastone of the heteroatoms is part of aromatic ring. The term “heteroaryl”is intended to include all the possible isomeric forms.

Thus, the term “heteroaryl” includes the following exemplary structureswhich are not depicted as radicals as each form may be attached througha covalent bond to any atom so long as appropriate valences aremaintained:

By the term “C₅-C₁₀-heteroaryl” (including those which are part of othergroups) are meant five- or six-membered heterocyclic aromatic groups or5-10-membered, bicyclic heteroaryl rings which may contain one, two, orthree heteroatoms selected from among oxygen, sulfur, and nitrogen, andcontain so many conjugated double bonds that an aromatic system isformed. The following are examples of five- or six- or nine-memberedheterocyclic aromatic groups:

Preferred are “C₅-C₆-heteroaryl” groups whereas aromatic rings are meantfive- or six-membered heterocyclic aromatic groups. Unless otherwisestated, these heteroaryls may be substituted by one or more groupsselected from among methyl, ethyl, isopropyl, tert-butyl, hydroxy,fluorine, chlorine, bromine, and iodine.

When a generic combined groups are used, for example —X—C₁-C₄-alkyl-with X being a functional group such as —CO—, —NH—, —C(OH)— and thelike, the functional group X can be located at either of the ends of the—C₁-C₄-alkyl chain.

By the term “spiro-C₃-C₈-cycloalkyl” (spiro) are meant 3-8 membered,spirocyclic rings while the ring is linked to the molecule through acarbon atom. By the term “spiro-C₃-C₈-heterocyclyl” (spiro) are meant3-8 membered, spirocyclic rings which may contain one, two, or threeheteroatoms selected from among oxygen, sulfur, and nitrogen, while thering may be linked to the molecule through a carbon atom or through anitrogen atom, if there is one.

Unless otherwise mentioned, a spirocyclic ring may be provided with anoxo, methyl, or ethyl group. Examples include:

“Halogen” within the scope of the present invention denotes fluorine,chlorine, bromine or iodine. Unless stated to the contrary, fluorine,chlorine and bromine are regarded as preferred halogens.

“Linker” within the scope of the present invention denominates abivalent group or a bond.

The above listed groups and residues can be combined to form morecomplex structures composed from carbon chains and rings or the like.

Compounds of general formula (I) may have acid groups, chiefly carboxylgroups, and/or basic groups such as e.g. amino functions. Compounds ofgeneral formula (I) may therefore occur as internal salts, as salts withpharmaceutically useable inorganic acids such as hydrochloric acid,sulphuric acid, phosphoric acid, sulphonic acid or organic acids (suchas for example maleic acid, fumaric acid, citric acid, tartaric acid oracetic acid) or as salts with pharmaceutically useable bases such asalkali or alkaline earth metal hydroxides or carbonates, zinc orammonium hydroxides or organic amines such as e.g. diethylamine,triethylamine, triethanolamine inter alia.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. For example,such salts include salts from ammonia, L-arginine, betaine, benethamine,benzathine, calcium hydroxide, choline, deanol, diethanolamine(2,2′-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol,2-aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine,1H-imidazole, lysine, magnesium hydroxide,4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide,1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine(2,2′,2″-nitrilotris(ethanol)), tromethamine, zinc hydroxide, aceticacid, 2,2-dichloro-acetic acid, adipic acid, alginic acid, ascorbicacid, L-aspartic acid, benzenesulfonic acid, benzoic acid,2,5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoric acid,(+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid,cyclamic acid, decanoic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, ethylenediaminetetraacetic acid, formicacid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonicacid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid,hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid,isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine,maleic acid, (−)-L-malic acid, malonic acid, DL-mandelic acid,methanesulfonic acid, galactaric acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid,palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionicacid, (−)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid,sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid. Further pharmaceutically acceptable salts can beformed with cations from metals like aluminium, calcium, lithium,magnesium, potassium, sodium, zinc and the like. (also seePharmaceutical salts, Berge, S. M. et al., J. Pharm. Sci., (1977), 66,1-19). The pharmaceutically acceptable salts of the present inventioncan be synthesized from the parent compound which contains a basic oracidic moiety by conventional chemical methods. Generally, such saltscan be prepared by reacting the free acid or base forms of thesecompounds with a sufficient amount of the appropriate base or acid inwater or in an organic diluent like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile, or a mixture thereof.

As mentioned hereinbefore, the compounds of formula (I) may be convertedinto the salts thereof, particularly for pharmaceutical use, into thephysiologically and pharmacologically acceptable salts thereof. Thesesalts may on the one hand be in the form of the physiologically andpharmacologically acceptable acid addition salts of the compounds offormula (I) with inorganic or organic acids. On the other hand, if R ishydrogen, the compound of formula (I) may also be converted by reactionwith inorganic bases into physiologically and pharmacologicallyacceptable salts with alkali or alkaline earth metal cations as counterion. The acid addition salts may be prepared for example usinghydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lacticacid, citric acid, tartaric acid or maleic acid. It is also possible touse mixtures of the above-mentioned acids. The alkali and alkaline earthmetal salts of the compound of formula (I) are preferably prepared usingthe alkali and alkaline earth metal hydroxides and hydrides thereof, ofwhich the hydroxides and hydrides of the alkaline earth metals,particularly of sodium and potassium, are preferred and sodium andpotassium hydroxide are particularly preferred.

If desired, the compounds of general formula (I) may be converted intothe salts thereof, particularly, for pharmaceutical use, into thepharmacologically acceptable acid addition salts with an inorganic ororganic acid. Suitable acids include for example succinic acid,hydrobromic acid, acetic acid, fumaric acid, maleic acid,methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid,sulphuric acid, tartaric acid or citric acid. It is also possible to usemixtures of the above-mentioned acids.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc. . . . ) and racematesthereof as well as mixtures in different proportions of the separateenantiomers, mixtures of diastereomers, or mixtures of any of theforegoing forms where such isomers and enantiomers exist, as well assalts, including pharmaceutically acceptable salts thereof and solvatesthereof such as for instance hydrates including solvates of the freecompounds or solvates of a salt of the compound.

Hence the invention relates to the compounds in question, optionally inthe form of the individual optical isomers, mixtures of the individualenantiomers or racemates, in the form of the tautomers as well as in theform of the free bases or the corresponding acid addition salts withpharmacologically acceptable acids—such as for example acid additionsalts with hydrohalic acids—for example hydrochloric or hydrobromic acidor organic acids—such as for example oxalic, fumaric, diglycolic ormethanesulphonic acid.

The compounds according to the invention may optionally occur asracemates, but they may also be obtained as pureenantiomers/diastereomers.

The invention relates to the compounds in question, optionally in theform of the individual optical isomers, mixtures of the individualenantiomers or racemates, in the form of the tautomers as well as in theform of the free bases or the corresponding acid addition salts withpharmacologically acceptable acids—such as for example acid additionsalts with hydrohalic acids—for example hydrochloric or hydrobromic acidor organic acids—such as for example oxalic, fumaric, diglycolic ormethanesulphonic acid.

The compounds according to formula (I) according to the invention havethe meanings hereinbefore whereas in particular the preferredembodiments defined by R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R_(8′), R₉,R_(9′), R₁₀, R₁₁, R_(11′)R₁₂, R₁₃, R_(13′), R₁₄, R₁₅, R_(15′)R₁₆, R₁₇,R₁₈, R₁₉, R₂₀, R_(20′), R₂₁, R_(21′), A, L₁, L₂, Z, Q, and n in eachcase are independently selected of one another.

Therapeutic Applications

The above exemplary substances have been tested for binding to CCR2using a binding assay as outlined herein below:

Cell Culture:

THP-1 cells (human acute monocytic leukaemia cells) were cultured understandardized conditions at 37° C. and 5% CO₂ in a humidified incubator.THP-1 cells were cultivated in RPMI 1640 medium (Gibco 21875) containing1% MEM-NEAA (Gibso 11140) 2 mM L-glutamine, 1.5 g/L sodium bicarbonate,4.5 g/L glucose, 10 mM HEPES and 1.0 mM sodium pyruvate, 90%; 10% fetalcalf serum (FCS Gibco 10500-064).

Membranes were prepared from THP-1 cells. THP-1 cells were centrifugedat 300×g at 4° C. for 10 min. The cell pellet was resuspended inPhosphate Buffer Saline (PBS, including 10 μM Pefabloc and a proteaseinhibitor mix ‘complete’, Boehringer Mannheim (1 tablet/50 ml)), to aconcentration of 80 cells/ml. The membrane preparation was performed bydisrupting the cells by nitrogen decomposition (at 50 bar, for 1 h) in a“Nitrogen Bombe” (Parr Instrument). Cell debris was removed bycentrifugation (800×g at 4° C., 1 min). The supernatant was centrifugedat 80000×g, 4° C. for 30 min to sediment the cell membranes. Usually 50mg of protein (Bradford assay) were yielded from 1×10E9 cells. Themembranes were resuspended in 25 mM HEPES, 25 mM MgCl₂, 1 mM CaCl₂, 10%Glycerine for storage in aliquots at −80° C. in 25 mM HEPES, 25 mMMgCl₂, 1 mM CaCl₂, 10% Glycerine and stored at −80° C.

Receptor Membrane Binding Assay:

Perkin Elmer NEX 332 Jod 125 MCP-1, Stock: 2200 Ci/mmol solved in 2000μl assay buffer, stored at −20° C. THP-1 membrane were adjusted with 25mM HEPES, pH 7.2; 5 mM MgCl2; 0.5 mM CaCl2; 0.2% BSA assay buffer to aconcentration of 2.5 μg/15 μl. Amersham Biosciences PVT-WGA Beads(RPNQ0001) were adjusted with assay buffer to a concentration of 0.24mg/30 μl. For preparation of the membrane-bead-suspension membranes andbeads were incubated for 30 min at RT under rotation (60 rpm) with aratio of 1:2. Test compounds dissolved in 100% DMSO to a concentrationof 10 mM and are further diluted with 100% DMSO to 1 mM. All additionalcompound dilutions were obtained with assay buffer, final 1% DMSO.Compounds, membrane-bead-suspension and [¹²⁵I]MCP-1 (ca. 25000 cpm/10μl) were incubated. Bound radioactivity was determined by scintillationcounter after 8 h. Determination of affinity of test compounds(dissociation constant hKi) is calculated by iterative fitting ofexperimental data using the “easy sys” program, which is based on law ofmass action (Schittkowski K. (1994), Numerische Mathematik, Vol. 68,129-142).

All of the referenced examples have been found to have an activity inthis assay of 10 μM or less.

Example hKi [nM] 1 60 2 40 3 1 4 10 5 3 6 4 7 1 8 2 9 27 10 3 11 16 120.7 13 35 14 5 15 6 16 3 17 73 18 7 19 9 20 54 21 41 22 4 23 128

Based on the ability of the substances described by formula (I) toeffectively bind to CCR2a range of therapeutic applications can beenvisaged. The present invention provides a method for modulating ortreating at least one MCP-1 related disease, in a cell, tissue, organ,animal, or patient, as known in the art or as described herein, using atleast one CCR2 antagonist of the present invention. The presentinvention also provides a method for modulating or treating at least oneMCP-1 related disease, in a cell, tissue, organ, animal, or patientincluding, but not limited to, at least one of malignant disease,metabolic disease, an immune or inflammatory related disease, acardiovascular disease, an infectious disease, or a neurologic disease.Such conditions are selected from, but not limited to, diseases orconditions mediated by cell adhesion and/or angiogenesis. Such diseasesor conditions include an immune disorder or disease, a cardiovasculardisorder or disease, an infectious, malignant, and/or neurologicdisorder or disease, or other known or specified MCP-1 relatedconditions. In particular, the CCR2 antagonists are useful for thetreatment of diseases that involve inflammation such as COPD,angiogenesis such as disease of the eye and neoplastic disease, tissueremodeling such as restenosis, and proliferation of certain cells typesparticularly epithelial and squamous cell carcinomas. Particularindications include use in the treatment of atherosclerosis, restenosis,cancer metastasis, rheumatoid arthritis, diabetic retinopathy andmacular degeneration. The antagonists may also be useful in thetreatment of various fibrotic diseases such as idiopathic pulmonaryfibrosis, diabetic nephropathy, hepatitis, and cirrhosis. Thus, thepresent invention provides a method for modulating or treating at leastone CCR2 related disease, in a cell, tissue, organ, animal, or patient,as known in the art or as described herein, using at least one CCR2antagonist of the present invention. Particular indications arediscussed below:

Pulmonary Diseases

The present invention also provides a method for modulating or treatingat least one malignant disease in a cell, tissue, organ, animal orpatient, including, but not limited to, at least one of: pneumonia; lungabscess; occupational lung diseases caused be agents in the form ordusts, gases, or mists; asthma, bronchiolitis fibrosa obliterans,respiratory failure, hypersensitivity diseases of the lungs iricludeinghypersensitivity pneumonitis (extrinsic allergic alveolitis), allergicbronchopulmonary aspergillosis, and drug reactions; adult respiratorydistress syndrome (ARDS), Goodpasture's Syndrome, chronic obstructiveairway disorders (COPD), idiopathic interstitial lung diseases such asidiopathic pulmonary fibrosis and sarcoidosis, desquamative interstitialpneumonia, acute interstitial pneumonia, respiratorybronchiolitis-associated interstitial lung disease, idiopathicbronchiolitis obliterans with organizing pneumonia, lymphocyticinterstitial pneumonitis, Langerhans' cell granulomatosis, idiopathicpulmonary hemosiderosis; acute bronchitis, pulmonary alveolar,proteinosis, bronchiectasis, pleural disorders, atelectasis, cysticfibrosis, and tumors of the lung, and pulmonary embolism.

Malignant Diseases

The present invention also provides a method for modulating or treatingat least one malignant disease in a cell, tissue, organ, animal orpatient, including, but not limited to, at least one of: leukemia, acuteleukemia, acute lymphoblastic leukemia (ALL), B-cell, T-cell or FAB ALL,acute myeloid leukemia (AML), chromic myelocytic leukemia (CML), chroniclymphocytic leukemia (CLL), hairy cell leukemia, myelodyplastic syndrome(MDS), a lymphoma, Hodgkin's disease, a malignant lymphoma,non-hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, Kaposi'ssarcoma, colorectal carcinoma, pancreatic carcinoma, renal cellcarcinoma, breast cancer, nasopharyngeal carcinoma, malignanthistiocytosis, paraneoplastic syndrome/hypercalcemia of malignancy,solid tumors, adenocarcinomas, squamous cell carcinomas, sarcomas,malignant melanoma, particularly metastatic melanoma, hemangioma,metastatic disease, cancer related bone resorption, cancer related bonepain, and the like.

Immune Related Diseases

The present invention also provides a method for modulating or treatingat least one immune related disease, in a cell, tissue, organ, animal,or patient including, but not limited to, at least one of rheumatoidarthritis, juvenile rheumatoid arthritis, systemic onset juvenilerheumatoid arthritis, psoriatic arthritis, ankylosing spondilitis,gastric ulcer, seronegative arthropathies, osteoarthritis, inflammatorybowel disease, ulcerative colitis, systemic lupus erythematosis,antiphospholipid syndrome, iridocyclitisluveitisloptic neuritis,idiopathic pulmonary fibrosis, systemic vasculitis/wegener'sgranulomatosis, sarcoidosis, orchitislvasectomy reversal procedures,allergiclatopic diseases, asthma, allergic rhinitis, eczema, allergiccontact dermatitis, allergic conjunctivitis, hypersensitivitypneumonitis, transplants, organ transplant rejection, graft-versus-hostdisease, systemic inflammatory response syndrome, sepsis syndrome, grampositive sepsis, gram negative sepsis, culture negative sepsis, fungalsepsis, neutropenic fever, urosepsis, meningococcemia,traumalhemo˜˜hage, burns, ionizing radiation exposure, acutepancreatitis, adult respiratory distress syndrome, rheumatoid arthritis,alcohol-induced hepatitis, chronic inflammatory pathologies,sarcoidosis, Crohn's pathology, sickle cell anemia, diabetes, nephrosis,atopic diseases, hypersensitity reactions, allergic rhinitis, hay fever,perennial rhinitis, conjunctivitis, endometriosis, asthma, urticaria,systemic anaphalaxis, dermatitis, pernicious anemia, hemolytic diseases,thrombocytopenia, graft rejection of any organ or tissue, kidneytransplant rejection, heart transplant rejection, liver transplantrejection, pancreas transplant rejection, lung transplant rejection,bone marrow transplant (BMT) rejection, skin allograft rejection,cartilage transplant rejection, bone graft rejection, small boweltransplant rejection, fetal thymus implant rejection, parathyroidtransplant rejection, xenograft rejection of any organ or tissue,allograft rejection, anti-receptor hypersensitivity reactions, Gravesdisease, Raynoud's disease, type B insulin-resistant diabetes, asthma,myasthenia gravis, antibody-meditated cytotoxicity, type IUhypersensitivity reactions, systemic lupus erythematosus, POEMS syndrome(polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy,and skin changes syndrome), polyneuropathy, organomegaly,endocrinopathy, monoclonal garnrnopathy, skin changes syndrome,antiphospholipid syndrome, pemphigus, scleroderma, mixed connectivetissue disease, idiopathic Addison's disease, diabetes mellitus, chronicactive hepatitis, primary billiary cirrhosis, vitiligo, vasculitis,post-MI cardiotomy syndrome, type IV hypersensitivity, contactdermatitis, hypersensitivity pneumonitis, allograft rejection,granulomas due to intracellular organisms, drug sensitivity,metabolic/idiopathic, Wilson's disease, hemachromatosis,alpha-1-antitrypsin deficiency, diabetic retinopathy, hashimoto'sthyroiditis, osteoporosis, hypothalamic-pituitary-adrenal axisevaluation, primary biliary cirrhosis, thyroiditis, encephalomyelitis,cachexia, cystic fibrosis, neonatal chronic lung disease, chronicobstructive pulmonary disease (COPD), familial hematophagocyticlymphohistiocytosis, dermatologic conditions, psoriasis, alopecia,nephrotic syndrome, nephritis, glomerular nephritis, acute renalfailure, hemodialysis, uremia, toxicity, preeclampsia, OKT3 therapy,anti-CD3 therapy, cytokine therapy, chemotherapy, radiation therapy(e.g., including but not limited toasthenia, anemia, cachexia, and thelike), chronic salicylate intoxication, and the like.

Cardiovascular Diseases

The present invention also provides a method for modulating or treatingat least one cardiovascular disease in a cell, tissue, organ, animal, orpatient, including, but not limited to, at least one of cardiac 25 stunsyndrome, myocardial infarction, congestive heart failure, stroke,ischemic stroke, hemorrhage, arteriosclerosis, atherosclerosis,restenosis, diabetic ateriosclerotic disease, hypertension, arterialhypertension, renovascular hypertension, syncope, shock, syphilis of thecardiovascular system, heart failure, cor pulmonale, primary pulmonaryhypertension, cardiac arrhythmias, atrial ectopic beats, atrial flutter,atrial fibrillation (sustained or paroxysmal), post perfusion syndrome,cardiopulmonary bypass inflammation response, chaotic or multifocalatrial tachycardia, regular narrow QRS tachycardia, specificarrythrnias, ventricular fibrillation, H is bundle arrythmias,atrioventricular block, bundle branch block, myocardial ischemicdisorders, coronary artery disease, angina pectoris, myocardialinfarction, cardiomyopathy, dilated congestive cardiomyopathy,restrictive cardiomyopathy, valvular heart diseases, endocarditis,pericardial disease, cardiac tumors, aordic and peripheral aneuryisms,aortic dissection, inflammation of the aorta, occulsion of the abdominalaorta and its branches, peripheral vascular disorders, occulsivearterial disorders, peripheral atherlosclerotic disease, thromboangitisobliterans, functional peripheral arterial disorders, Raynaud'sphenomenon and disease, acrocyanosis, erythromelalgia, venous diseases,venous thrombosis, varicose veins, arteriovenous fistula, lymphederma,lipedema, unstable angina, reperfusion injury, post pump syndrome,ischemia-reperfusion injury, and the like. Such a method can optionallycomprise administering an effective amount of a composition orpharmaceutical composition comprising at least one CCR2 antagonist to acell, tissue, organ, animal or patient in need of such modulation,treatment or therapy.

Neurologic Diseases

The present invention also provides a method for modulating or treatingat least one neurologic disease in a cell, tissue, organ, animal orpatient, including, but not limited to, at least one of: Inflammatorypain, chronic pain, Neuropathic pain such as low back pain, hip pain,leg pain, non-herpetic neuralgia, post herpetic neuralgia, diabeticneuropathy, nerve injury-induced pain, acquired immune deficiencysyndrome (AIDS) related neuropathic pain, head trauma, toxin andchemotherapy caused nerve injuries, phantom limb pain, multiplesclerosis, root avulsions, painful traumatic mononeuropathy, painfulpolyneuropathy, thalamic pain syndrome, post-stroke pain, centralnervous system injury, post surgical pain, carpal tunnel syndrome,trigeminal neuralgia, post mastectomy syndrome, postthoracotomysyndrome, stump pain, repetitive motion pain, neuropathic painassociated hyperalgesia and allodynia, alcoholism and other drug-inducedpain; neurodegenerative diseases, multiple sclerosis, migraine headache,AIDS dementia complex, demyelinating diseases, such as multiplesclerosis and acute transverse myelitis; extrapyramidal and cerebellardisorders' such as lesions of the corticospinal system; disorders of thebasal ganglia or cerebellar disorders; hyperkinetic movement disorderssuch as Huntington's Chorea and senile chorea; drug-induced movementdisorders, such as those induced by drugs which block CNS dopaminereceptors; hypokinetic movement disorders, such as Parkinson's disease;Progressive supra-nucleo Palsy; structural lesions of the cerebellum;spinocerebellar degenerations, such as spinal ataxia, Friedreich'sataxia, cerebellar cortical degenerations, multiple systemsdegenerations (Mencel, Dejerine-Thomas, Shi-Drager, and Machado-Joseph);systemic disorders (Refsum's disease, abetalipoprotemia, ataxia,telangiectasia, and mitochondrial multi.system disorder); demyelinatingcore disorders, such as multiple sclerosis, acute transverse myelitis;and disorders of the motor unit' such as neurogenic muscular atrophies(anterior horn cell degeneration, such as amyotrophic lateral sclerosis,infantile spinal muscular atrophy and juvenile spinal muscular atrophy);Alzheimer's disease; Down's Syndrome in middle age; Diffuse Lewy bodydisease; Senile Dementia of Lewy body type; Wernicke-Korsakoff syndrome;chronic alcoholism; Creutzfeldt-Jakob disease; Subacute sclerosingpanencephalitis, Hallerrorden-Spatz disease; and Dementia pugilistica,and the like.

Fibrotic Conditions

In addition to the above described conditions and diseases, the presentinvention also provides a method for modulating or treating fibroticconditions of various etiologies such as liver fibrosis (including butnot limited to alcohol-induced cirrhosis, viral-induced cirrhosis,autoimmune-induced hepatitis); lung fibrosis (including but not limitedto scleroderma, idiopathic pulmonary fibrosis); kidney fibrosis(including but not limited to scleroderma, diabetic nephritis,glomerular pehpritis, lupus nephritis); dermal fibrosis (including butnot limited to scleroderma, hypertrophic and keloid scarring, burns);myelofibrosis; Neurofibromatosis; fibroma; intestinal fibrosis; andfibrotic adhesions resulting from surgical procedures.

The present invention also provides a method for modulating or treatingat least one wound, trauma or tissue injury or chronic conditionresulting from or related thereto, in a cell, tissue, organ, animal orpatient, including, but not limited to, at least one of: bodily injuryor a trauma associated with surgery including thoracic, abdominal,cranial, or oral surgery; or

wherein the wound is selected from the group consisting of asepticwounds, contused wounds, incised wounds, lacerated wounds,non-penetrating wounds, open wounds, penetrating wounds, perforatingwounds, puncture wounds, septic wounds, infarctions and subcutaneouswounds; or wherein the wound is selected from the group consisting ofischemic ulcers, pressure sores, fistulae, severe bites, thermal burnsand donor site wounds; or wherein the wound is anaphthous wound, atraumatic wound or a herpes associated wound. Donor site wounds arewounds which e.g. occur in connection with removal of hard tissue fromone part of the body to another part of the body e.g. in connection withtransplantation. The wounds resulting from such operations are verypainful and an improved healing is therefore most valuable. Woundfibrosis is also amenable to CCR2 antagonist therapy as the first cellsto invade the wound area are neutrophils followed by monocytes which areactivated by macrophages. Macrophages are believed to be essential forefficient wound healing in that they also are responsible forphagocytosis of pathogenic organisms and a clearing up of tissue debris.Furthermore, they release numerous factors involved in subsequent eventsof the healing process. The macrophages attract fibroblasts which startthe production of collagen. Almost all tissue repair processes includethe early connective tissue formation, a stimulation of this and thesubsequent processes improve tissue healing, however, overproduction ofconnective tissue and collegen can lead to a fibrotic tissuecharacterized as inelastic and hypoxic. The CCR2 antagonist of theinvention can be used in methods for modulating, treating or preventingsuch sequelae of wound healing.

Other Therapeutic Uses of CCR2 Antagonists

The present invention also provides a method for modulating or treatingat least one infectious disease in a cell, tissue, organ, animal orpatient, including, but not limited to, at least one of: acute orchronic bacterial infection, acute and chronic parasitic or infectiousprocesses, including bacterial, viral and fungal infections, HIVinfection, HIV neuropathy, meningitis, hepatitis (A, B or C, or thelike), septic arthritis, peritonitis, pneumonia, epiglottitis, e. coli0157:h7, hemolytic uremic syndrome/thrombolytic thrombocytopenicpurpura, malaria, dengue hemorrhagic fever, leishmaniasis, leprosy,toxic shock syndrome, streptococcal myositis, gas gangrene,mycobacterium tuberculosis, mycobacterium avium intracellulare,pneumocystis carinii pneumonia, pelvic inflammatory disease,orchitislepidydimitis, legionella, lyme disease, influenza a,epstein-barr virus, vital-associated hemaphagocytic syndrome, vitalencephalitisiaseptic meningitis, and the like.

Any method of the present invention can comprise administering aneffective amount of a composition or pharmaceutical compositioncomprising at least one CCR2 antagonist to a cell, tissue, organ, animalor patient in need of such modulation, treatment or therapy.

Besides being useful for human treatment, these compounds are alsouseful for veterinary treatment of companion animals, exotic animals andfarm animals, including mammals, rodents, and the like.

Combinations

The compounds of formula (I) may be used on their own or in conjunctionwith other active substances of formula (I) according to the invention.If desired the compounds of formula (I) may also be used in combinationwith other pharmacologically active substances. It is preferable to usefor this purpose active substances selected for example from amongβ2-adrenoceptor-agonists (short and ion-acting betamimetics),anti-cholinergics (short and ion-acting), anti-inflammatory steroids(oral and topical corticosteroids), cromoglycate, methylxanthine,dissociated-glucocorticoidmimetics, PDE3 inhibitors, PDE4-inhibitors,PDE7-inhibitors, LTD4 antagonists, EGFR-inhibitors, Dopamine agonists,statins, PAF antagonists, Lipoxin A4 derivatives, FPRL1 modulators,LTB4-receptor (BLT1, BLT2) antagonists, Histamine H1 receptorantagonists, Histamine H4 receptor antagonists, dual HistamineH1/H3-receptor antagonists, PI3-kinase inhibitors, inhibitors ofnon-receptor tyrosine kinases as for example LYN, LCK, SYK (spleentyrosine kinase-inhibitors), ZAP-70, FYN, BTK or ITK, inhibitors of MAPkinases as for example p38, ERK1, ERK2, JNK1, JNK2, JNK3 or SAP,inhibitors of the NF-kappaB signalling pathway as for example IKK2kinase inhibitors, iNOS inhibitors (inducible nitric oxidesynthase-inhibitors), MRP4 inhibitors, leukotriene antagonists,leukotriene biosynthese inhibitors as for example 5-Lipoxygenase (5-LO)inhibitors, cPLA2 inhibitors, Leukotriene A4 Hydrolase inhibitors orFLAP inhibitors, non-steroidal antiinfiammatory drugs (NSAIDs) includingCOX-2 inhibitors, CRTH2 antagonists, DP1-receptor modulators,Thromboxane receptor antagonists, CCR1 antagonists, CCR4 antagonists,CCR5 antagonists, CCR6 antagonists, CCR7 antagonists, CCR8 antagonists,CCR9 antagonists, CCR10 antagonists, CCR11 antagonists, CXCR1antagonists, CXCR2 antagonists, CXCR3 antagonists, CXCR4 antagonists,CXCR5 antagonists, CXCR6 antagonists, CX3CR1 antagonists, Neurokinin(NK1, NK2) antagonists, Sphingosine 1-Phosphate receptor modulators,Sphingosine 1 phosphate lyase inhibitors, Adenosine receptor modulatorsas for example A2a-agonists, modulators of purinergic rezeptors as forexample P2X7 inhibitors, Histone Deacetylase (HDAC) activators,Bradykinin (BK1, BK2) antagonists, TACE inhibitors, PPAR gammamodulators, Rho-kinase inhibitors, interleukin 1-beta converting enzyme(ICE) inhibitors, Toll-Like receptor (TLR) modulators, HMG-CoA reductaseinhibitors, VLA-4 antagonists, ICAM-1 inhibitors, SHIP agonists, GABAareceptor antagonist, ENaC-inhibitors, Melanocortin receptor (MC1R, MC2R,MC3R, MC4R, MC5R) modulators, CGRP antagonists, Endothelin antagonists,TNFalpha antagonists, anti-TNF antibodies, anti-GM-CSF antibodies,anti-CD46 antibodies, anti-IL-1 antibodies, anti-IL-2 antibodies,anti-IL-4 antibodies, anti-IL-5 antibodies, anti-IL-13 antibodies,anti-IL-4/IL-13 antibodies, anti-TSLP antibodies, anti-OX40 antibodies,mucoregulators, immunotherapeutic agents, compounds agianst swelling ofthe airways, compounds against cough, antiviral drugs, opiate receptoragonists, cannabionoid agonists, sodium channel blockers, N-type calciumchannel blockers, serotonergic and noradrenergic modulators, proton pumpinhibitors, local anesthetics, VR1 agonists and antagonists, Nicotinicacetylcholine receptor agonists, P2X3 receptor antagonists, NGF agonistsand antagonists, NMDA antagonist, potassium channel modulators, GABAmodulators, serotonergic and noradrenergic modulators, anti-migrainedrugs. The invention also encompasses combinations of three activesubstances, each selected from one of the above-mentioned categories ofcompounds. Said list is not considered to have a limiting character. Thebetamimetics used are preferably compounds selected from amongalbuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol,fenoterol, formoterol, arformoterol, zinterol, hexoprenaline, ibuterol,isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine,metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol,rimiterol, ritodrine, salmeterol, salmefamol, soterenol, sulphonterol,tiaramide, terbutaline, tolubuterol, CHF-1035, HOKU-81, KUL-1248,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulphonamide,5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone, 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazo-3-yl]-2-methyl-2-butylamino}ethanol,5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one,1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol,6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetateethyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-aceticacid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyricacid,8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneand1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol,optionally in the form of the racemates, enantiomers, diastereomersthereof and optionally in the form of the pharmacologically acceptableacid addition salts, solvates or hydrates thereof.

Preferably the beta mimetics are selected from among bambuterol,bitolterol, carbuterol, clenbuterol, fenoterol, formoterol,hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol,sulphonterol, terbutaline, tolubuterol,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide,5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone, 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazo-3-yl]-2-methyl-2-butylamino}ethanol,5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one,1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol,6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetateethyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-aceticacid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyricacid,8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneand1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol,optionally in the form of the racemates, enantiomers, diastereomersthereof and optionally in the form of the pharmacologically acceptableacid addition salts, solvates or hydrates thereof.

Particularly preferred betamimetics are selected from among fenoterol,formoterol, salmeterol,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide,5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetateethyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-aceticacid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyricacid,8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneand1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,optionally in the form of the racemates, enantiomers, diastereomersthereof and optionally in the form of the pharmacologically acceptableacid addition salts, solvates or hydrates thereof.

Of these betamimetics those which are particularly preferred accordingto the invention are formoterol, salmeterol,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide,6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(ethyl4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-aceticacid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyricacid,8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneand5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,optionally in the form of the racemates, enantiomers, diastereomersthereof and optionally in the form of the pharmacologically acceptableacid addition salts, solvates or hydrates thereof.

According to the invention the acid addition salts of the betamimeticsare preferably selected from among hydrochloride, hydrobromide,hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate,hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate,hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoateand hydro-p-toluenesulphonat, preferably hydrochloride, hydrobromide,hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.Of the above-mentioned acid addition salts the salts of hydrochloricacid, methanesulphonic acid, benzoic acid and acetic acid areparticularly preferred according to the invention.

The anticholinergics used are preferably compounds selected from amongthe tiotropium salts, oxitropium salts, flutropium salts, ipratropiumsalts, glycopyrronium salts, trospium salts, tropenol2,2-diphenylpropionate methobromide, scopine 2,2-diphenylpropionatemethobromide, scopine 2-fluoro-2,2-diphenylacetate methobromide,tropenol 2-fluoro-2,2-diphenylacetate methobromide, tropenol3,3′,4,4′-tetrafluorobenzilate methobromide, scopine3,3′,4,4′-tetrafluorobenzilate methobromide, tropenol4,4′-difluorobenzilate methobromide, scopine 4,4′-difluorobenzilatemethobromide, tropenol 3,3′-difluorobenzilate methobromide, -scopine3,3′-difluorobenzilate methobromide, tropenol9-hydroxy-fluorene-9-carboxylate-methobromide, tropenol9-fluoro-fluorene-9-carboxylate-methobromide, scopine9-hydroxy-fluoren-9-carboxylate methobromide, scopine9-fluoro-fluorene-9-carboxylate methobromide, tropenol9-methyl-fluorene-9-carboxylate methobromide, scopine9-methyl-fluorene-9-carboxylate methobromide, cyclopropyltropinebenzilate methobromide, cyclopropyltropine 2,2-diphenylpropionatemethobromide, cyclopropyltropine 9-hydroxy-xanthene-9-carboxylatemethobromide, cyclopropyltropine 9-methyl-fluorene-9-carboxylatemethobromide, cyclopropyltropine 9-methyl-xanthene-9-carboxylatemethobromide, cyclopropyltropine 9-hydroxy-fluorene-9-carboxylatemethobromide, methyl -cyclopropyltropine 4,4′-difluorobenzilatemethobromide, tropenol 9-hydroxy-xanthene-9-carboxylate-methobromide,scopine 9-hydroxy-xanthene-9-carboxylate methobromide, tropenol9-methyl-xanthene-9-carboxylate methobromide, scopine9-methyl-xanthene-9-carboxylate methobromide, tropenol9-ethyl-xanthene-9-carboxylate methobromide, tropenol9-difluoromethyl-xanthene-9-carboxylate methobromide, scopine9-hydroxymethyl-xanthene-9-carboxylate methobromide, optionally in theform of the solvates or hydrates thereof.

In the above-mentioned salts the cations tiotropium, oxitropium,flutropium, ipratropium, glycopyrronium and trospium are thepharmacologically active ingredients. As anions, the above-mentionedsalts may preferably contain chloride, bromide, iodide, sulphate,phosphate, methanesulphonate, nitrate, maleate, acetate, citrate,fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate,while chloride, bromide, iodide, sulphate, methanesulphonate orp-toluenesulphonate are preferred as counter-ions. Of all the salts, thechlorides, bromides, iodides and methanesulphonate are particularlypreferred.

Of particular importance is tiotropium bromide. In the case oftiotropium bromide the pharmaceutical combinations according to theinvention preferably contain it in the form of the crystallinetiotropium bromide monohydrate, which is known from WO 02/30928. If thetiotropium bromide is used in anhydrous form in the pharmaceuticalcombinations according to the invention, it is preferable to useanhydrous crystalline tiotropium bromide, which is known from WO03/000265.

Corticosteroids used here are preferably compounds selected from amongprednisolone, prednisone, butixocortpropionate, flunisolide,beclomethasone, triamcinolone, budesonide, fluticasone, mometasone,ciclesonide, rofleponide, dexamethasone, betamethasone, deflazacort,RPR-106541, NS-126, (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionateand (S)-(2-oxo-tetrahydro-furan-3 S-yl)6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate,optionally in the form of the racemates, enantiomers or diastereomersthereof and optionally in the form of the salts and derivatives,solvates and/or hydrates thereof.

Particularly preferred is the steroid selected from among flunisolide,beclomethasone, triamcinolone, budesonide, fluticasone, mometasone,ciclesonide, rofleponide, dexamethasone, NS-126, (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionateand (S)-(2-oxo-tetrahydro-furan-3S-yl)6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate,optionally in the form of the racemates, enantiomers or diastereomersthereof and optionally in the form of the salts and derivatives,solvates and/or hydrates thereof.

Particularly preferred is the steroid selected from among budesonide,fluticasone, mometasone, ciclesonide and (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate,optionally in the form of the racemates, enantiomers or diastereomersthereof and optionally in the form of the salts and derivatives,solvates and/or hydrates thereof.

Any reference to steroids includes a reference to any salts orderivatives, hydrates or solvates thereof which may exist. Examples ofpossible salts and derivatives of the steroids may be: alkali metalsalts, such as for example sodium or potassium salts, sulphobenzoates,phosphates, isonicotinates, acetates, propionates, dihydrogenphosphates, palmitates, pivalates or furoates thereof.

PDE4 inhibitors which may be used are preferably compounds selected fromamong enprofyllin, theophyllin, roflumilast, ariflo (cilomilast),tofimilast, pumafentrin, lirimilast, arofyllin, atizoram, D-4396(Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418,PD-168787, T-440, T-2585, V-11294A, CI-1018, CDC-801, CDC-3052, D-22888,YM-58997, Z-15370,N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide,(−)_(p)-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide,(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone,3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N-2-cyano-5-methyl-isothioureido]benzyl)-2-pyrrolidone,cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid],2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-one,cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol],(R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,(S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridineand9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,optionally in the form of the racemates, enantiomers or diastereomersand optionally in the form of the pharmacologically acceptable acidaddition salts, solvates and/or hydrates thereof.

The PDE4-inhibitor used are preferably compounds selected from amongenprofyllin, roflumilast, ariflo (cilomilast), arofyllin, atizoram,AWD-12-281 (GW-842470), T-440, T-2585, PD-168787, V-11294A, CI-1018,CDC-801, D-22888, YM-58997, Z-15370,N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide,cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid],2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one,cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol],9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridineand9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,optionally in the form of the racemates, enantiomers or diastereomersand optionally in the form of the pharmacologically acceptable acidaddition salts, solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theabove-mentioned PDE4-inhibitors might be in a position to form aremeant, for example, salts selected from among the hydrochloride,hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferablyhydrochloride, hydrobromide, hydrosulphate, hydrophosphate,hydrofumarate and hydromethanesulphonate.

LTD4-antagonists which may be used are preferably compounds selectedfrom among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523),MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321,1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-aceticacid,1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane-aceticacid and[2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]aceticacid, optionally in the form of the racemates, enantiomers ordiastereomers, optionally in the form of the pharmacologicallyacceptable acid addition salts and optionally in the form of the saltsand derivatives, solvates and/or hydrates thereof.

Preferably the LTD4-antagonist is selected from among montelukast,pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507),VUF-5078, VUF-K-8707 and L-733321, optionally in the form of theracemates, enantiomers or diastereomers, optionally in the form of thepharmacologically acceptable acid addition salts and optionally in theform of the salts and derivatives, solvates and/or hydrates thereof.

Particularly preferably the LTD4-antagonist is selected from amongmontelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001 andMEN-91507 (LM-1507), optionally in the form of the racemates,enantiomers or diastereomers, optionally in the form of thepharmacologically acceptable acid addition salts and optionally in theform of the salts and derivatives, solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theLTD4-antagonists may be capable of forming are meant, for example, saltsselected from among the hydrochloride, hydrobromide, hydroiodide,hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide,hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.By salts or derivatives which the LTD4-antagonists may be capable offorming are meant, for example: alkali metal salts, such as, forexample, sodium or potassium salts, alkaline earth metal salts,sulphobenzoates, phosphates, isonicotinates, acetates, propionates,dihydrogen phosphates, palmitates, pivalates or furoates.

EGFR-inhibitors which may be used are preferably compounds selected fromamong4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-11-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-11-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-11-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin,3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline,4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,Cetuximab, Trastuzumab, ABX-EGF and Mab ICR-62, optionally in the formof the racemates, enantiomers or diastereomers thereof, optionally inthe form of the pharmacologically acceptable acid addition salts, thesolvates and/or hydrates thereof.

Preferred EGFR inhibitors are selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine,3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline,4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,

-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-[l    1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,    4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,    4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline,    4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,    4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,    4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,    4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline,    4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,    4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydro    furan-2-yl)methoxy]-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,    4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,    and Cetuximab, optionally in the form of the racemates, enantiomers    or diastereomers thereof, optionally in the form of the    pharmacologically acceptable acid addition salts, the solvates    and/or hydrates thereof.

Preferable the EGFR-inhibitors are selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine,3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,and4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,optionally in the form of the racemates, enantiomers or diastereomersthereof, optionally in the form of the pharmacologically acceptable acidaddition salts, the solvates and/or hydrates thereof.

EGFR-inhibitors are preferably selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazolineand4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazolineoptionally in the form of the racemates, enantiomers or diastereomersthereof, optionally in the form of the pharmacologically acceptable acidaddition salts, the solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theEGFR-inhibitors may be capable of forming are meant, for example, saltsselected from among the hydrochloride, hydrobromide, hydroiodide,hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide,hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.

Examples of dopamine agonists which may be used preferably includecompounds selected from among bromocriptine, cabergoline,alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol,ropinirol, talipexol, terguride and viozan. Any reference to theabove-mentioned dopamine agonists within the scope of the presentinvention includes a reference to any pharmacologically acceptable acidaddition salts and optionally hydrates thereof which may exist. By thephysiologically acceptable acid addition salts which may be formed bythe above-mentioned dopamine agonists are meant, for example,pharmaceutically acceptable salts which are selected from the salts ofhydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lacticacid, citric acid, tartaric acid and maleic acid.

Examples of H1-antihistamines preferably include compounds selected fromamong epinastine, cetirizine, azelastine, fexofenadine, levocabastine,loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine,bamipin, cexchlorpheniramine, pheniramine, doxylamine,chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine,ebastine, desloratidine and meclozine. Any reference to theabove-mentioned H1-antihistamines within the scope of the presentinvention includes a reference to any pharmacologically acceptable acidaddition salts which may exist.

Examples of PAF-antagonists preferably include compounds selected fromamong4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepines,6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclo-penta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepines.

MRP4-inhibitors used are preferably compounds selected from amongN-acetyl-dinitrophenyl-cysteine, cGMP, cholate, diclofenac,dehydroepiandrosterone 3-glucuronide, dehydroepiandrosterone 3-sulphate,dilazep, dinitrophenyl-s-glutathione, estradiol 17-β-glucuronide,estradiol 3,17-disulphate, estradiol 3-glucuronide, estradiol3-sulphate, estrone 3-sulphate, flurbiprofen, folate,N5-formyl-tetrahydrofolate, glycocholate, clycolithocholic acidsulphate, ibuprofen, indomethacin, indoprofen, ketoprofen, lithocholicacid sulphate, methotrexate, MK571((E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoicacid), α-naphthyl-β-D-glucuronide, nitrobenzyl mercaptopurine riboside,probenecid, PSC833, sildenafil, sulfinpyrazone, taurochenodeoxycho late,taurocholate, taurodeoxycholate, taurolithocholate, taurolithocholicacid sulphate, topotecan,

trequinsin and zaprinast, dipyridamole, optionally in the form of theracemates, enantiomers, diastereomers and the pharmacologicallyacceptable acid addition salts and hydrates thereof.

MRP4-inhibitors are preferably selected from amongN-acetyl-dinitrophenyl-cysteine, dehydroepiandrosterone 3-sulphate,dilazep, dinitrophenyl-5-glutathione, estradiol 3,17-disulphate,flurbiprofen, glycocholate, glycolithocholic acid sulphate, ibuprofen,indomethacin, indoprofen, lithocholic acid sulphate, MK571, PSC833,sildenafil, taurochenodeoxycho late, taurocholate, taurolithocholate,taurolithocholic acid sulphate, trequinsin and zaprinast, dipyridamole,optionally in the form of the racemates, enantiomers, diastereomers andthe pharmacologically acceptable acid addition salts and hydratesthereof.

Particularly preferred MRP4-inhibitors are selected from amongdehydroepiandrosterone 3-sulphate, estradiol 3,17-disulphate,flurbiprofen, indomethacin, indoprofen, MK571, taurocholate, optionallyin the form of the racemates, enantiomers, diastereomers and thepharmacologically acceptable acid addition salts and hydrates thereof.The separation of enantiomers from the racemates can be carried outusing methods known from the art (e.g. chromatography on chiral phases,etc.).

By acid addition salts with pharmacologically acceptable acids aremeant, for example, salts selected from among the hydrochlorides,hydrobromides, hydroiodides, hydrosulphates, hydrophosphates,hydromethanesulphonates, hydronitrates, hydromaleates, hydroacetates,hydrobenzoates, hydrocitrates, hydrofumarates, hydrotartrates,hydrooxalates, hydrosuccinates, hydrobenzoates andhydro-p-toluenesulphonates, preferably the hydrochlorides,hydrobromides, hydrosulphates, hydrophosphates, hydrofumarates andhydromethanesulphonates.

The invention further relates to pharmaceutical preparations whichcontain a triple combination of the CCR2 inhibitors, MRP4-inhibitors andanother active substance according to the invention, such as, forexample, an anticholinergic, a steroid, an LTD4-antagonist or abetamimetic, and the preparation thereof and the use thereof fortreating respiratory complaints.

The iNOS-inhibitors used are preferably compounds selected from among:S-(2-aminoethyl)isothiourea, aminoguanidine, 2-aminomethylpyridine, AMT,L-canavanine, 2-iminopiperidine, S-isopropylisothiourea,S-methylisothiourea, S-ethylisothiourea, S-methyltiocitrulline,S-ethylthiocitrulline, L-NA (N^(ω)-nitro-L-arginine), L-NAME(N^(ω)-nitro-L-arginine methylester), L-NMMA(N^(G)-monomethyl-L-arginine), L-NIO (N^(ω)-iminoethyl-L-ornithine),L-NIL (N^(ω)-iminoethyl-lysine), (S)-6-acetimidoylamino-2-amino-hexanoicacid (1H-tetrazol-5-yl)-amide (SC-51) (J. Med. Chem. 2002, 45,1686-1689), 1400W,(S)-4-(2-acetimidoylamino-ethylsulphanyl)-2-amino-butyric acid(GW274150) (Bioorg. Med. Chem. Lett. 2000, 10, 597-600),2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine(BYK191023) (Mol. Pharmacol. 2006, 69, 328-337),2-((R)-3-amino-1-phenyl-propoxy)-4-chloro-5-fluorobenzonitrile (WO01/62704),2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-6-trifluoromethyl-nicotinonitrile(WO 2004/041794),2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-4-chloro-benzonitrile(WO 2004/041794),2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-benzonitrile(WO 2004/041794),(2S,4R)-2-amino-4-(2-chloro-5-trifluoromethyl-phenylsulphanyl)-4-thiazol-5-yl-butan-1-ol(WO 2004/041794),2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-nicotinonitrile(WO 2004/041794),4-((S)-3-amino-4-hydroxy-1-phenyl-butylsulphanyl)-6-methoxy-nicotinonitrile(WO 02/090332), substituted 3-phenyl-3,4-dihydro-1-isoquinolinaminessuch as e.g. AR-C102222 (J. Med. Chem. 2003, 46, 913-916),(1S,5S,6R)-7-chloro-5-methyl-2-aza-bicyclo[4.1.0]hept-2-en-3-ylamine(ONO-1714) (Biochem. Biophys. Res. Commun. 2000, 270, 663-667),(4R,5R)-5-ethyl-4-methyl-thiazo lidin-2-ylideneamine (Bioorg. Med. Chem.2004, 12, 4101), (4R,5R)-5-ethyl-4-methyl-selenazolidin-2-ylideneamine(Bioorg. Med. Chem. Lett. 2005, 15, 1361), 4-aminotetrahydrobiopterine(Curr. Drug Metabol. 2002, 3, 119-121),(E)-3-(4-chloro-phenyl)-N-(1-{2-oxo-2-[4-(6-trifluoromethyl-pyrimidin-4-yloxy)-piperidin-1-yl]-ethylcarbamoyl}-2-pyridin-2-yl-ethyl)-acrylamide(FR260330) (Eur. J. Pharmacol. 2005, 509, 71-76),3-(2,4-difluoro-phenyl)-6-[2-(4-imidazol-1-ylmethyl-phenoxy)-ethoxy]-2-phenyl-pyridine(PPA250) (J. Pharmacol. Exp. Ther. 2002, 303, 52-57), methyl3-{[(benzo[1,3]dioxol-5-ylmethyl)-carbamoyl]-methyl}-4-(2-imidazol-1-yl-pyrimidin-4-yl)-piperazin-1-carboxylate(BBS-1) (Drugs Future 2004, 29, 45-52),(R)-1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidine-2-carboxylicacid (2-benzo[1,3]dioxol-5-yl-ethyl)-amide (BBS-2) (Drugs Future 2004,29, 45-52) and the pharmaceutical salts, prodrugs or solvates thereof.

Compounds which may be used as SYK-inhibitors are preferably compoundsselected from among: R343 or R788.

Examples of preferred MAP kinase inhibitors, as for example p38, ERK1,ERK2, JNK1, JNK2, JNK3 or SAP, which may be mentioned include SCIO-323,SX-011, SD-282, SD-169, NPC-037282, SX-004, VX-702, GSK-681323,GSK-856553, ARRY-614, ARRY-797, ARRY-438162, ARRY-p38-002, ARRY-371797,AS-602801, AS-601245, AS-602183, CEP-1347, KC706, TA-5493, RO-6226,Ro-1487, SC-409, CBS-3595, VGX-1027, PH-797804, BMS-582949, TA-5493 andBIRB-796 optionally in racemic form, as enantiomers, diastereomeres oras pharmacologically acceptable salts, solvates or hydrates.

Examples of preferred inhibitors of the NF-κB signalling pathwayincluding IKK2 kinase inhibitors which may be mentioned include:MD-1041, MLN-041 und AVE-0547 optionally in racemic form, asenantiomers, diastereomeres or as pharmacologically acceptable salts,solvates or hydrates.

Examples of preferred Leukotriene biosynthesis inhibitors, as forexample 5-Lipoxygenase (5-LO) inhibitors, cPLA2 inhibitors, LeukotrieneA4 hydrolase inhibitors oder FLAP inhibitors, which may be mentionedinclude zileuton, tipelukast, licofelone, darapladib, TA-270, IDEA-033,IDEA-070, NIK-639, ABT-761, fenleuton, tepoxalin, AM-103, AM-803,Abbott-79175, Abbott-85761, PLT-3514, CMI-903, PEP-03, CMI-977, MLN-977,CMI-947, LDP-977, efipladib, PLA-695, veliflapon, MK-591, MK-886 undBAYx1005 optionally in racemic form, as enantiomers, diastereomeres oras pharmacologically acceptable salts, solvates or hydrates.

Examples of preferred non-steroidal anti-inflammatory agents (NSAIDs)which may be mentioned include COX-2 inhibitors: propionic acidderivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen,fenhufen, fenoprofen, flubiprofen, ibuprofen, indoprofen, ketoprofen,miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen,tiaprofenic acid, and tioxaprofen), acetic acid derivatives(indomethacin, acemetacin, alclofenac, clidanac, diclofenac,fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac,oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac),fenamic acid derivatives (meclofenamic acid, mefenamic acid, andtolfenamic acid), biphenyl-carboxylic acid derivatives, oxicams(isoxicam, meloxicam, piroxicam, sudoxicam and tenoxican), salicylates(acetyl salicylic acid, sulfasalazine) and the pyrazolones (apazone,bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone),and the coxibs (celecoxib, valecoxib, rofecoxib and etoricoxib)optionally in racemic form, as enantiomers, diastereomeres or aspharmacologically acceptable salts, solvates or hydrates.

Examples of preferred CCR1 antagonists which may be mentioned includeAZD-4818, CCX-354, MLN-3701, MLN-3897, optionally in racemic form, asenantiomers, diastereomeres or as pharmacologically acceptable salts,solvates or hydrates.

Examples of preferred CCR5 antagonists which may be mentioned includemaraviroc, INCB-15050. CCR5 mAb004, GSK-706769, PRO-140, SCH-532706,vicriviroc and nifeviroc optionally in racemic form, as enantiomers,diastereomeres or as pharmacologically acceptable salts, solvates orhydrates.

Examples of preferred CXCR1 or CXCR2 antagonists which may be mentionedinclude SCH-527123 and SB-656933 optionally in racemic form, asenantiomers, diastereomeres or as pharmacologically acceptable salts,solvates or hydrates.

Examples of preferred Neurokinin (NK1 or NK2) antagonists which may bementioned include Saredutant, Nepadutant, PRX-96026 und Figopitantoptionally in racemic form, as enantiomers, diastereomeres or aspharmacologically acceptable salts, solvates or hydrates.

Examples of preferred purinergic receptor modulators, including P2X7inhibitors, which may be mentioned include AZD-9056 optionally inracemic form, as enantiomers, diastereomeres or as pharmacologicallyacceptable salts, solvates or hydrates.

Examples of preferred PPAR gamma modulators which may be mentionedinclude Rosiglitazone, Ciglitazone, Pioglitazone and SMP-028 optionallyin racemic form, as enantiomers, diastereomeres or as pharmacologicallyacceptable salts, solvates or hydrates.

Examples of preferred Interleukin 1-beta converting enzyme (ICE)inhibitors which may be mentioned include Pralnacasan, VRT-18858,RU-36384, VX-765 and VRT-43198 optionally in racemic form, asenantiomers, diastereomeres or as pharmacologically acceptable salts,solvates or hydrates.

Examples of preferred Toll-like receptor (TLR) modulators which may bementioned include Resiquimod, PF-3512676, AVE-0675, Heplisav, IMO-2055,CpG-28, TAK-242, SAR-21609, RC-52743198 and 852A optionally in racemicform, as enantiomers, diastereomeres or as pharmacologically acceptablesalts, solvates or hydrates.

Examples of preferred VLA4 antagonists which may be mentioned includeNatalizumab, Valategrast, TBC-4746, CDP-323 and TL-1102 optionally inracemic form, as enantiomers, diastereomeres or as pharmacologicallyacceptable salts, solvates or hydrates.

Examples of preferred ICAM-1 inhibitors which may be mentioned includeBIRT-2584 optionally in racemic form, as enantiomers, diastereomeres oras pharmacologically acceptable salts, solvates or hydrates.

Examples of preferred anti-TNF antibodies which may be mentioned includeInfliximab, Adalimumab, Golimumab. CytoFab and Etanercept.

Examples of preferred mucoregulators which may be mentioned includeMSI-2216, Erdosteine, Fluorovent, Talniflumate, INO-4995, BIO-11006,VR-496 and fudosteine optionally in racemic form, as enantiomers,diastereomeres or as pharmacologically acceptable salts, solvates orhydrates.

Examples of preferred Antiviral drugs which may be mentioned includeacyclovir, tenovir, pleconaril, peramivir, pocosanol.

Examples of preferred Antibiotic drugs like gentamicin, streptomycin,geldanamycin, doripenem, cephalexin, cefaclor, ceftazichine, cefepime,erythromycin, vancomycin, aztreonam, amoxicillin, bacitracin, enoxacin,mafenide, doxycycline, chloramphenicol.

Examples of preferred opiate receptor agonists are selected from amongmorphine, propoxyphene (Darvon), tramadol, buprenorphin.

Examples of preferred anti-TNF antibodies or TNF-receptor antagonistssuch as but not limited to Etanercept, Infliximab, Adalimumab (D2E7),CDP 571, and Ro 45-2081 (Lenercept), or biologic agents directed againsttargets such as but not limited to CD-4, CTLA-4, LFA-1, IL-6, ICAM-1, C5and Natalizumab.

Examples of preferred IL-1 receptor antagonists such as but not limitedto Kineret; Sodium channel blockers: carbamazepine, mexiletine,lamotrigine, tectin, lacosamide

Examples of preferred N-type calcium channel blockers are selected fromamong Ziconotide.

Examples of preferred Serotonergic and noradrenergic modulators such asbut not limited to paroxetine, duloxetine, clonidine, amitriptyline,citalopram;

Examples of preferred Histamine H1 receptor antagonists such as but notlimited to bromophtniramint, chlorpheniramine, dexchlorpheniramine,triprolidine, clemastine, diphenhydramine, diphenylpyraline,tripelennamine, hydroxyzine, methdiJazine, promethazine, trimeprazine,azatadine, cyproheptadine, antazoline, pheniramine pyrilamine,astemizole, terfenadine, loratadine, cetirizine, deslo-ratadine,fexofenadine and levocetirizine.

Examples of preferred Histamine H2 receptor antagonists such as but notlimited to cimetidine, famotidine and ranitidine.

Examples of preferred proton pump inhibitors such as but not limited toomeprazole, pantoprazole and esomeprazole.

Examples of preferred Leukotriene antagonists and 5-lipoxygenaseinhibitors such as but not limited to zafirlukast, montelukast,pranlukast and zileuton.

Examples of preferred local anesthetics such as but not limited toambroxol, lidocaine.

Examples of preferred potassium channel modulators such as but notlimited to retigabine.

Examples of preferred GABA modulators such as but not limited tolacosamide, pregabalin, gabapentin.

Examples of preferred anti-migraine drugs such as but not limited tosumatriptan, zolmitriptan, naratriptan, eletriptan, telcegepant.

Examples of preferred NGF antibodies such as but not limited to RI724.

Combination therapy is also possible with new principles for thetreatment of pain e.g. P2X3 antagonists, VR1 antagonists, NK1 and NK2antagonists, NMDA antagonists, mGluR antagonists and the like.

Pharmaceutical Formulations

Suitable forms for administration are for example tablets, capsules,solutions, syrups, emulsions or inhalable powders or aerosols. Thecontent of the pharmaceutically effective compound(s) in each caseshould be in the range from 0.1 to 90 wt. %, preferably 0.5 to 50 wt. %of the total composition, i.e. in amounts which are sufficient toachieve the dosage range specified hereinafter.

The preparations may be administered orally in the form of a tablet, asa powder, as a powder in a capsule (e.g. a hard gelatine capsule), as asolution or suspension. When administered by inhalation the activesubstance combination may be given as a powder, as an aqueous oraqueous-ethanolic solution or using a propellant gas formulation.

Preferably, therefore, pharmaceutical formulations are characterised inthat they contain one or more compounds of formula (I) according to thepreferred embodiments above.

It is particularly preferable if the compounds of formula (I) areadministered orally, and it is also particularly preferable if they areadministered once or twice a day. Suitable tablets may be obtained, forexample, by mixing the active substance(s) with known excipients, forexample inert diluents such as calcium carbonate, calcium phosphate orlactose, disintegrants such as corn starch or alginic acid, binders suchas starch or gelatine, lubricants such as magnesium stearate or talcand/or agents for delaying release, such as carboxymethyl cellulose,cellulose acetate phthalate, or polyvinyl acetate. The tablets may alsocomprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups containing the active substances or combinations thereofaccording to the invention may additionally contain a sweetener such assaccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. aflavouring such as vanillin or orange extract. They may also containsuspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

For oral administration the tablets may, of course, contain, apart fromthe above-mentioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

It is also preferred if the compounds of formula (I) are administered byinhalation, particularly preferably if they are administered once ortwice a day. For this purpose, the compounds of formula (I) have to bemade available in forms suitable for inhalation. Inhalable preparationsinclude inhalable powders, propellant-containing metered-dose aerosolsor propellant-free inhalable solutions, which are optionally present inadmixture with conventional physiologically acceptable excipients.

Within the scope of the present invention, the term propellant-freeinhalable solutions also includes concentrates or sterile ready-to-useinhalable solutions. The preparations which may be used according to theinvention are described in more detail in the next part of thespecification.

Inhalable Powders

If the active substances of formula (I) are present in admixture withphysiologically acceptable excipients, the following physiologicallyacceptable excipients may be used to prepare the inhalable powdersaccording to the invention: monosaccharides (e.g. glucose or arabinose),disaccharides (e.g. lactose, saccharose, maltose), oligo- andpolysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol,xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures ofthese excipients with one another. Preferably, mono- or disaccharidesare used, while the use of lactose or glucose is preferred,particularly, but not exclusively, in the form of their hydrates. Forthe purposes of the invention, lactose is the particularly preferredexcipient, while lactose monohydrate is most particularly preferred.Methods of preparing the inhalable powders according to the invention bygrinding and micronising and by finally mixing the components togetherare known from the prior art.

Propellant-Containing Inhalable Aerosols

The propellant-containing inhalable aerosols which may be used accordingto the invention may contain the active substances of formula (I)dissolved in the propellant gas or in dispersed form. The propellantgases which may be used to prepare the inhalation aerosols according tothe invention are known from the prior art. Suitable propellant gasesare selected from among hydrocarbons such as n-propane, n-butane orisobutane and halohydrocarbons such as preferably fluorinatedderivatives of methane, ethane, propane, butane, cyclopropane orcyclobutane. The propellant gases mentioned above may be used on theirown or in mixtures thereof. Particularly preferred propellant gases arefluorinated alkane derivatives selected from TG134a(1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane)and mixtures thereof. The propellant-driven inhalation aerosols usedwithin the scope of the use according to the invention may also containother ingredients such as co-solvents, stabilisers, surfactants,antioxidants, lubricants and pH adjusters. All these ingredients areknown in the art.

Propellant-Free Inhalable Solutions

The compounds of formula (I) according to the invention are preferablyused to prepare propellant-free inhalable solutions and inhalablesuspensions. Solvents used for this purpose include aqueous oralcoholic, preferably ethanolic solutions. The solvent may be water onits own or a mixture of water and ethanol. The solutions or suspensionsare adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids.The pH may be adjusted using acids selected from inorganic or organicacids. Examples of particularly suitable inorganic acids includehydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/orphosphoric acid. Examples of particularly suitable organic acids includeascorbic acid, citric acid, malic acid, tartaric acid, maleic acid,succinic acid, fumaric acid, acetic acid, formic acid and/or propionicacid etc. Preferred inorganic acids are hydrochloric and sulphuricacids. It is also possible to use the acids which have already formed anacid addition salt with one of the active substances. Of the organicacids, ascorbic acid, fumaric acid and citric acid are preferred. Ifdesired, mixtures of the above acids may also be used, particularly inthe case of acids which have other properties in addition to theiracidifying qualities, e.g. as flavourings, antioxidants or complexingagents, such as citric acid or ascorbic acid, for example. According tothe invention, it is particularly preferred to use hydrochloric acid toadjust the pH. Co-solvents and/or other excipients may be added to thepropellant-free inhalable solutions used for the purpose according tothe invention. Preferred co-solvents are those which contain hydroxylgroups or other polar groups, e.g. alcohols—particularly isopropylalcohol, glycols—particularly propyleneglycol, polyethyleneglycol,polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols andpolyoxyethylene fatty acid esters. The terms excipients and additives inthis context denote any pharmacologically acceptable substance which isnot an active substance but which can be formulated with the activesubstance or substances in the pharmacologically suitable solvent inorder to improve the qualitative properties of the active substanceformulation. Preferably, these substances have no pharmacological effector, in connection with the desired therapy, no appreciable or at leastno undesirable pharmacological effect. The excipients and additivesinclude, for example, surfactants such as soya lecithin, oleic acid,sorbitan esters, such as polysorbates, polyvinylpyrrolidone, otherstabilisers, complexing agents, antioxidants and/or preservatives whichguarantee or prolong the shelf life of the finished pharmaceuticalformulation, flavourings, vitamins and/or other additives known in theart. The additives also include pharmacologically acceptable salts suchas sodium chloride as isotonic agents. The preferred excipients includeantioxidants such as ascorbic acid, for example, provided that it hasnot already been used to adjust the pH, vitamin A, vitamin E,tocopherols and similar vitamins or provitamins occurring in the humanbody. Preservatives may be used to protect the formulation fromcontamination with pathogens. Suitable preservatives are those which areknown in the art, particularly cetyl pyridinium chloride, benzalkoniumchloride or benzoic acid or benzoates such as sodium benzoate in theconcentration known from the prior art. For the treatment formsdescribed above, ready-to-use packs of a medicament for the treatment ofrespiratory complaints are provided, containing an enclosed descriptionincluding for example the words respiratory disease, COPD or asthma, apteridine and one or more combination partners selected from thosedescribed above.

EXPERIMENTAL PROCEDURES AND SYNTHETIC EXAMPLES List of Abbreviations

-   ACN acetonitrile-   APCI atmospheric pressure chemical ionization (in MS)-   Ctrl control-   DAD diode array detector-   DMA N,N-dimethylacetamide-   DMF N,N-dimethylformamide-   DMSO dimethyl sulfoxide-   EI electron impact (in MS)-   ESI electrospray ionization (in MS)-   ex example-   GC/MS gas chromatography with mass spectrometric detection-   h hour(s)-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluoro-phosphate-   HPLC high performance liquid chromatography-   HPLC/MS coupled high performance liquid chromatography-mass    spectrometry-   min minutes-   MS mass spectrometry-   NMP N-Methyl-2-pyrrolidinone-   NMR nuclear magnetic resonance-   R_(t) retention time (in HPLC)-   sec secondary-   TBTU O-(1H-benzo-1,2,3-triazol-1-yl)-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   tert tertiary-   TFA trifluoroacetic acid-   THF tetrahydrofurane-   TLC thin-layer chromatography-   UV ultraviolet absorption

Analytical Methods HPLC Methods Methods:

2Ca

Column: MERCK; Chromolith Flash; RP18e; 25×4.6 mm

Mobile phase: A=water+0.1% HCOOH; B=ACN+0.1% HCOOH

Flow rate: 1.6 ml/min

Gradient:

A % B % Time [min] 90 10 0.00 10 90 2.70 10 90 3.00 90 10 3.30

Equipment

Instrument: Agilent Technology; HP 1100 Series, DAD

Detection: UV 190-400 nm

Detection: Agilent Technology; HP 1100 MSD

Ion source: ESI+

Methods:

2 Cc

Column: MERCK; Chromolith Flash; RP18e; 25×4.6 mm, at 60° C.

Mobile: A=water+0.1% HCOOH; B=MeOH

Flow rate: 2.5 ml/min

Gradient:

A % B % Time [min] 90 10 0.00 0 100 1.61 0 100 2.25

Equipment

Instrument: Agilent Technology; HP 1200 Series, DAD

Detection: UV 190-400 nm

Detection: Agilent Technology; 1200 MSD

Ion source: ESI+

Methods:

2I (isocratic)

Column: DAICEL AS-H 5 μm, 4.6×250 mm

Mobile phase: A=Hexane; B=EtOH (con AS-H), IPA (con AD-H)

-   -   A/B=98/2%

Flow rate: 1 ml/min

2Ia (isocratic)

Column: DAICEL Chiralpack AS-H 5 μm, 4.6×250 mm

Mobile phase: A=Hexane; B=EtOH

-   -   A/B=98/2%

Flow rate: 1 ml/min

2Ja (isocratic)

Column: DAICEL Chiralpack AD-H 5 μm, 4.6×250 mm

Mobile phase: A=Hexane; B=Isopropanol

-   -   A/B=80/20%

Flow rate: 1 ml/min

2Ka (isocratic)

Column: DAICEL Chiralcel OJ-H 5 μm, 4.6×250 mm

Mobile phase: A=Hexane; B=EtOH

-   -   A/B=98/2%

Flow rate: 1 ml/min

Equipment

Instrument: LC Agilent Technologies. HPLC 1100 Serie, DAD Version A.

Detection: UV 220-300 nm

Methods:

Y1 1

Column: Waters; XBridge C18, 4.6×30 mm, 3.5 μm, at 60° C.

Mobile: A=water+0.1% TFA; B=MeOH+0.1% TFA

Gradient:

A % B % Time [min] Flow rate [ml/min] 95 5 0.00 4 95 5 0.15 4 0 100 1.704 0 100 2.25 4

Y8 1

Column: Waters; Sunfire C18, 4.6×30 mm, 3.5 μm, at 60° C.

Mobile: A=water+0.1% HCOOH; B=MeOH

Gradient:

A % B % Time [min] Flow rate [ml/min] 95 5 0.00 4 95 5 0.15 4 0 100 1.704 0 100 2.25 4

Equipment:

Instrument: Agilent Technology; 1100 Series, DAD

Detection: UV 210-400 nm

Detection: Agilent Technology; 1100 MSD

Ion source: ESI+

Method:

Z1 2

Column: Waters; XBridge C18, 3×30 mm, 2.5 μm, at 60° C.

Mobile: A=water+0.2% TFA; B=MeOH

Gradient:

A % B % Time [min] Flow rate [ml/min] 95 5 0.00 2.2 95 5 0.05 2.2 0 1001.40 2.2 0 100 1.80 2.2

Equipment:

Instrument: Agilent Technology; 1200 Series, DAD

Detection: UV 210-400 nm

Detection: Agilent Technology; 1200 MSD

Ion source: ESI+

GC-MS methods:

Methods:

3A

Column: Agilent DB-5MS, 25 m×0.25 mm×0.25 μm

Carrier gas: Helium, 1 ml/min costant flow

Oven Program: 50° C. (hold 1 min.), to 100° C. in 10° C./min, to 200° C.in 20° C./min, to 300° C. in 30° C./min

3B

Column: Agilent DB-5MS, 25 m×0.25 mm×0.25 μm

Carrier gas: Helium, 1 ml/min costant flow

Oven Program: 80° C. to 110° C. in 10° C./min (hold 40 min), to 280° C.in 30° C./min

Equipment

Instrument: GC/MS Finnigan TRACE GC, TRACE MS quadrupole

Detection: TRACE MS quadrupole

Ion source: EI

Synthesis of Intermediates Intermediate 1

Commercially available (R)-3-phenylcyclohexanone (2.0 g, 11.48 mmol) and1-isocyanomethanesulfonyl-4-methyl-benzene (2.91 g, 14.92 mmol) in 10 mlof 1,2-dimethoxyethane were stirred at 0° C. A solution of potassiumtert-butoxide (2.57 g, 22.96 mmol) in 10 ml 1,2-dimethoxyethane and 20ml tert-butanol was added dropwise and the reaction mixture was allowedto reach room temperature and stirred overnight. The reaction mixturewas diluted with diethyl ether and washed with ice water. The organicphase was separated, washed with brine, dried over sodium sulfate andconcentrated under vacuum. 2.1 g (11.2 mmol) of the desired product wereobtained.

GC/MS (method 3A) R_(t)=11.52 min and 11.68 min (diastereoisomericmixture) [M]⁺=185

Intermediate 2

Intermediate 1 (2.1 g, 11.2 mmol) was stirred under reflux in 20 ml of96% sulfuric acid and 20 ml water overnight. The reaction mixture wascooled, treated with a 30% aqueous solution of sodium hydroxide and iceand washed with dichloromethane. The basic water phase was treated with37% aqueous solution of hydrochloric acid. The acidic aqueous solutionwas extracted with dichloromethane. The organic phase was washed withbrine, dried over sodium sulfate and concentrated under vacuum. 1.85 g(9.1 mmol) of the desired compound were obtained as a diastereoisomericmixture and used in the next steps without further purification.

Intermediate 3a

Intermediate 2 (1.85 g, 9.06 mmol, mixture of 2 diastereomers) andtriethylamine (2.02 ml, 14 mmol) were stirred at 0° C. in 10 mltetrahydrofuran. A solution of ethylchloroformate (1.29 ml, 13.58 mmol)in 5 ml tetrahydrofuran was added dropwise and the reaction mixture wasstirred at 0° C. for 1 h. Then, 10 ml of a 30% aqueous solution ofammonium hydroxide were added dropwise and the reaction mixture wasallowed to reach room temperature and stirred overnight. The reactionmixture was concentrated under vacuum, dissolved with dichloromethane,washed with a 1M aqueous solution of sodium hydroxide, washed withbrine, dried over sodium sulfate and concentrated under vacuum. Thecrude product was purified by flash chromatography (Isolute silicacartridge 70 g; eluent: dichloromethane/methanol=99/1%). 145 mg (0.71mmol) of diastereoisomerically pure(1R,3R)-3-phenyl-cyclohexanecarboxylic acid amide (relativestereochemistry assigned by NMR) were obtained.

GC/MS (method 3A) R_(t)=12.88 min

[M]⁺=203

Intermediate 3b

Further elution of the column gave 230 mg (1.13 mmol) of thediastereoisomerically pure (1S,3R)-3-phenyl-cyclohexanecarboxylic acidamide (relative stereochemistry assigned by NMR).

GC/MS (method 3A) R_(t)=13.03 min

[M]⁺=203

Intermediate 4

4.53 ml of a 1M solution of lithium aluminium hydride (4.53 mmol) intetrahydrofuran was dissolved in 30 ml tetrahydrofuran and stirred at 0°C. under nitrogen atmosphere. Intermediate 3b (230 mg, 1.13 mmol) in 10ml tetrahydrofuran was added dropwise. The reaction mixture was stirredat 0° C. for 2 h and then quenched with water and ice. The reactionmixture was extracted with dichlorometane. The organic phase was washedwith a 1M aqueous solution of sodium hydroxide, brine, dried over sodiumsulfate and concentrated under vacuum. 180 mg (0.95 mmol) of the desiredproduct were obtained.

GC/MS (method 3A) R_(t)=11.47 min [M]⁺=189

Intermediate 5a

To a solution of lithium bromide (24 g, 277.1 mmol) in 500 ml of drytetrahydrofurane, stirred under nitrogen atmosphere, copper(I) bromide(19.87 g, 138.5 mmol) was added. The reaction mixture was stirred atroom temperature until a solution was obtained. Then, the reactionmixture was cooled to 0° C. and a 0.5M solution of commerciallyavailable 4-tolyl magnesium bromide in THF (277.1 ml, 138.5 mmol) wasadded. Then, commercially available 4-chlorocarbonyl-butyric acid ethylester (19 g, 115.4 mmol) was added and the reaction mixture was stirredat 0° C. for 18 h.

500 ml of a saturated aqueous ammonium chloride solution was added andthe reaction mixture was extracted twice with dichloromethane. Theorganic phase was washed with a saturated aqueous sodium bicarbonatesolution, dried over sodium sulfate and concentrated under vacuum. Thecrude product (20 g) was used in the next step without any purification.

Intermediate 6a

To a solution of intermediate 5a (20 g, 90.8 mmol) in 50 ml oftetrahydrofurane 50 ml of water and lithium hydroxide monohydrate (11.43g, 274.40 mmol) were added and the reaction mixture was stirred at 50°C. for 1 h.

The reaction mixture was extracted with ethyl acetate and the layerswere separated. The aqueous layer was acidified with aqueous HCl (37%)until pH 1 and then extracted with dichloromethane. The organic layerwas dried over sodium sulfate and concentrated under vacuum. The crudeproduct was triturated with diisopropyl ether. The solvent was removedby filtration yielding the desired product (13 g, 63.1 mmol).

Intermediate 7a

A suspension of intermediate 6a (11.5 g, 55.8 mmol) in 250 ml water wascooled to 10°. Then, potassium hydroxide (7.82 g, 139.4 mmol) and sodiumborohydride (1.83 g, 48.5 mmol) were added and the reaction mixture wasallowed to reach room temperature and stirred for 2 h. 13 ml of a 12Maqueous hydrochloric acid was added and the reaction mixture wasextracted with ethyl acetate. The organic layer was dried over sodiumsulfate and concentrated under vacuum to give the crude product (11 g,52.8 mmol).

The following intermediates were synthesized in analogy to Intermediates5a, 6a and 7a.

Hydroxy- Keto-ester Keto-acid acid Starting Inter- Inter- Inter-Grignard mediate STRUCTURE mediate STRUCTURE mediate STRUCTURE4-((Trifluoro- methyl)-phenyl)- magnesium bromide 5b

6b

7b

4-((Trifluoro- methoxy)-phenyl)- magnesium bromide 5c

6c

7c

Intermediate 8a

Intermediate 7a (6 g, 28.8 mmol) was dissolved in 100 ml ofdichloromethane. 1.5 ml trifluoroacetic acid were added and the reactionmixture was stirred at room temperature for 18 h. The reaction mixturewas diluted with 50 ml of dichloromethane and washed with 50 ml of asaturated aqueous sodium bicarbonate solution and water. The organiclayer was dried over sodium sulfate and removed under vacuum to give thedesired product (4.38 g, 23.0 mmol).

Intermediate 9a

A solution of intermediate 8a (4.38 g, 23.0 mmol) in 110 ml ofdichloromethane was cooled to −78° C. Then, a 1M solution ofdiisobutylaluminiumhydride (46.15 ml, 46.15 mmol) in dichloromethane wasadded dropwise. The reaction mixture was stirred at −78° C. for 2 h. 100ml of methanol were added at −78° C. and the reaction mixture wasallowed to reach room temperature. The reaction mixture was concentratedunder vacuum and the crude product obtained was triturated with ethylether. The precipitate was filtered off and washed with diethyl ether.The organic layer was removed under vacuum to give the crude lactol (4.4g, 22.9 mmol). The lactol was dissolved in 80 ml of dry dichloromethaneand cooled to 0° C. Then, triethylamine (4.96 ml, 34.3 mmol), aceticanhydride (2.54 ml, 27.5 mmol) and 4-dimethylaminopyridine (279.6 mg,2.3 mmol) were added. The reaction mixture was allowed to reach roomtemperature and stirred for 1 h. A saturated aqueous sodium bicarbonatesolution was added and the mixture was extracted with dichloromethane.The organic phase was dried over sodium sulfate and concentrated undervacuum. The residue was purified by flash chromatography (Biotage SP1cartridge 50 g, eluent: cyclohexane/ethyl acetate=95/5) to give thedesired product (4 g, 17.1 mmol).

The following intermediates were synthesized in analogy to Intermediates8a and 9a.

Starting Lactone Hydroxy- Inter- Lactol-acetate acid Intermediatemediate STRUCTURE Intermediate STRUCTURE 7b 8b

9b

7c 8c

9c

Intermediate 10a

Trimethylsilylcyanide (0.52 ml, 4.16 mmol) and borontrifluoride etherate(0.27 ml, 2.2 mmol) were added to a solution of intermediate 9a (650 mg,2.77 mmol) in 50 ml of acetonitrile under nitrogen atmosphere at roomtemperature. The reaction mixture was stirred for 18 h. The reactionmixture was concentrated under vacuum to give the desired product(mixture of diastereoisomers).

GC/MS (method 3A) R_(t)=10.47 min and 10.68 min (diastereoisomericmixture, ratio trans/cis=8/2)

Intermediate 11a

Intermediate 10a was purified by flash chromatography (Biotage SP1cartridge 25 g, eluent: cyclohexane/ethyl acetate=99/1). 400 mg ofdiastereomerically pure trans stereoisomer was obtained (racemate,relative configuration assigned by NMR).

GC/MS (method 3A) R_(t)=10.47 min

Intermediate 12a

Further elution of the column gave 100 mg of the diastereomerically purecis stereoisomer (racemate, relative configuration assigned by NMR).

GC/MS (method 3A) R_(t)=10.68 min

Intermediate 12a was also obtained by epimerization of Intermediate 11a:Intermediate 11a (3.2 g, 15 mmol) was dissolved in 40 ml oftetrahydrofurane. Potassium tert-butoxide (178 mg, 1 mmol) was added andthe reaction mixture was stirred at room temperature for 0.5 h. Thesolid was removed by filtration and the reaction mixture wasconcentrated under vacuum. The crude product was purified by flashchromatography (Biotage SP1 cartridge 50 g, eluent: cyclohexane/ethylacetate=99/1). 1.45 g of the desired cis diastereoisomer were obtained.

The following intermediates were synthesized in analogy to Intermediates10a, 11a and 12a.

Starting Lactol- acetate Intermediate Intermediate STRUCTUREIntermediate STRUCTURE Intermediate STRUCTURE 9b 10b

11b

12b

9c 10c

11c

12c

Intermediate 13a

Racemic Intermediate 12a (1.17 g, 2.06 mmol) was separated by chiralHPLC (semi-preparative column). 400 mg (2.0 mmol) were obtained assingle enantiomer.

Chiral HPLC (method 21 isocratic): R_(t)=8.74 min

Intermediate 14a

Further elution of the column gave 390 mg (1.94 mmol) of thecorresponding single enantiomer.

Chiral HPLC (method 21 isocratic): R_(t)=9.06 min

Absolute stereochemistry was determined by X-ray crystallography:

Absolute stereochemistry was derived from the refinement of anomalousdispersion data.

While an unambiguous assignment is not possible due to the lack of heavyatoms, the Flack parameter gave a clear tendency toward the indicatedchiral configuration.

Crystal Data: C₁₃H₁₅N₁O₁M_(r)=201.26, orthorhombic, P2₁2₁2₁,a=8.0519(16)Å, b=11.185(2)Å, c=12.637(3)Å, V=1138.2(4)Å³, Z=4,D_(X)=1.175 g/cm³, l=1.542 Å, m=0.58 mm⁻¹, F(000)=423, T=100(1) K. DataCollection: 12235 measured reflections, 1888/1130 unique, Rint=0.079.Refinement: 138 parameters; hydrogen atoms were included as ridingatoms, S=1.02, R1=0.052 for 1393 reflections with Fo>4sig(Fo), wR=0.128(Weight w=1/[s²(Fo²)+(0.0864P)²+0.0P] where P=(Fo²+2Fc²)/3, largestdifference peak: 0.31 e/Å³; largest difference hole −0.22 e/Å³,Flack=0.2(5).

The following intermediates were separated in analogy to Intermediates13a and 14a.

Second Starting Chiral First Single syn- HPLC Single R_(t) syn- R_(t)racemate Method syn-stereoisomer (min) STRUCTURE stereoisomer (min)STRUCTURE Stereochemistry 12b 2Ia 13b 13.25

14b 14.33

determined determined by X-ray crystallography* 12c 2Ka 13c 13.65

14c 14.53

relative stereochemistry cis *Absolute stereochemistry for intermediate13b was derived from the refinement of anomalous dispersion data. Whilean unambiguous assignment is not possible due to the lack of heavyatoms, the Flack parameter gave a clear tendency toward the indicatedchiral configuration. Crystal Data: C₁₃ H₁₂ N₁ O₁ F₃, M_(r) = 255.24,orthorhombic, P2₁2₁2₁, a = 7.5726(15)Å, b = 11.053(2)Å, c = 14.173(3)Å,V = 1186.3(4)Å³, Z = 4, D_(X) = 1.429 g/cm³, 1 = 1.542 Å, m = 1.061mm⁻¹, F(000) = 528, T = 100(1) K. Data Collection: 8980 measuredreflections, 1900/1131 unique, Rint = 0.045. Refinement: 164 parameters;hydrogen atoms were included as riding atoms, S = 1.10, R1 = 0.065 for1710 reflections with Fo > 4sig(Fo), wR = 0.167 (Weight w = 1/[s²(Fo²) +(0.1147P)² + 1.0917P] where P = (Fo² + 2Fc²)/3, largest difference peak:0.43 e/Å³; largest difference hole −0.39 e/Å³, Flack = 0.2(3).

Intermediate 15a

Intermediate 10a was dissolved in 20 ml of tetrahydrofurane, a 1Msolution of borane-tetrahydrofurane complex (3.28 ml, 3.28 mmol) wasadded and the reaction mixture was stirred at room temperature for 18 h.20 ml of a saturated aqueous sodium bicarbonate solution and 50 ml ofdicholometane were added. The organic layer was dried over magnesiumsulfate and concentrated under vacuum. 90 mg (0.44 mmol) of the desiredproduct were obtained.

Intermediate 16a

was synthesized in analogy to Intermediate 15a starting fromintermediate 12a.

Intermediate 17a

was synthesized in analogy to Intermediate 15a starting fromintermediate 13a (absolute stereochemistry as shown).

Intermediate 18a

was synthesized in analogy to intermediate 15a starting fromintermediate 14a (absolute stereochemistry as shown).

The following intermediates were synthesized in analogy to Intermediates17a, 18a.

Starting Inter- Starting Inter- Inter- medi- inter- medi- Stereo-mediate ate STRUCTURE mediate ate STRUCTURE chemistry 13b 17b

14b 18b

as shown 13c 17c

14c 18c

relative stereo- chemistry cis

Intermediate 19a

N-methyl-N-piperidin-4-yl-methanesulfonamide hydrochloride (11 g, 47.91mmol; WO2009/47161) was suspended in 200 ml of 1,2-dichloroethane,N,N-diisopropylethylamine (17.12 ml, 96.17 mmol) and commerciallyavailable 1-(tert-butoxycarbonyl)-piperidin-4-one (9.58 g, 48.08 mmol)were added and the reaction mixture was stirred at room temperature for30 min. Sodium triacetoxyborohydride (12.23 g, 57.50 mmol) was added andthe reaction mixture was stirred at room temperature for 72 h. Thereaction mixture was diluted with dichloromethane and washed with anaqueous saturated sodium bicarbonate solution. The organic phase wasdried over sodium sulfate and concentrated under vacuum. The crudeproduct was purified by flash chromatography (Biotage SP; silica gelcartridge: 65i; eluent: ethyl acetate/methanol=50/50%) to obtain 7.2 g(19.2 mmol) of the desired compound.

Intermediate 20a

Intermediate 19a (7.2 g, 19.2 mmol) was suspended in 20 ml of1,4-dioxane, a 4M solution of hydrochloric acid (48 ml, 192 mmol) in1,4-dioxane was added dropwise. The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated undervacuum. 6.3 g (18 mmol) of the desired compound were obtained.

The following intermediates were synthesized in analogy to Intermediates19a and 20a.

Carbamate Diamino Source/ Starting Source/ Inter- Inter- Startingintermediate Reference intermediate Reference mediate STRUCTURE mediateSTRUCTURE 1-(tert- butoxycarbonyl)- 4-oxopiperidine commerciallyavailable 22b — 19b

20b

1-(tert- butoxycarbonyl)- 4-oxopiperidine commercially available 22c —19c

20c

3-Methoxy- tetrahydro- pyran-4-one Tetrahedron Letters, 2005, 447-4504-amino- piperidine-1- carboxylic acid tert-butyl-ester Commerciallyavailable 19d

20d

3-Fluoro- tetrahydro- pyran-4-one WO2003/ 93231 4-amino- piperidine-1-carboxylic acid tert-butyl-ester Commercially available 19e

20e

Intermediate 21b

3-Methoxy-tetrahydro-pyran-4-one* (1 g, 7.68 mmol), commerciallyavailable (R)-(+)-1-phenylethylamine (0.99 ml, 7.68 mmol) andRaney-Nickel (200 mg) in 10 ml of dry ethanol were stirred under ahydrogen atmosphere (5 bar) for 15 days. The reaction mixture wasdiluted with 20 ml of methanol and 20 ml of tetrahydrofurane, stirredfor 15 minutes, filtered on a celite pad and concentrated under vacuum.The crude product was loaded on a SCX cartridge (50 g). The cartridgewas washed with methanol and the desired product was eluted with a 7 Msolution of ammonia in methanol. The basic organic phase wasconcentrated under vacuum and the crude product was purified by flashchromatography (dichloromethane/methanol=98/2%) to obtain 710 mg (3.02mmol) of the desired product as single stereoisomer (diastereoisomericpurity confirmed and relative cis configuration assigned by NMR).

GC/MS (method 3B) R_(t)=35.04 min

*Tetrahedron Letters, 2005, 447-450

Intermediate 21c

was synthesised in analogy to Intermediate 21b, starting from3-Methoxy-tetrahydro-pyran-4-one and commercially available(S)-(−)-1-phenylethylamine (diastereoisomeric purity confirmed andrelative cis configuration assigned by NMR).

GC/MS (method 3B) R_(t)=35.04 min

Intermediate 22b

Intermediate 21b (1.18 g, 5.01 mmol), Pd/C 10% (200 mg) and acetic acid(0.3 ml, 5.01 mmol) in 20 ml of methanol were stirred under a hydrogenatmosphere (5 bar) for 18 h. The reaction mixture was diluted with 20 mlof methanol, stirred for 15 minutes, filtered on a celite pad andconcentrated under vacuum. The crude product was loaded on a SCXcartridge (50 g). The cartridge was wash with methanol and the desiredproduct was eluted with a 7 M solution of ammonia in methanol. The basicorganic phase was concentrated under vacuum and 513 mg (3.91 mmol) ofthe desired product were obtained as single stereoisomer

Intermediate 22c

was synthesised in analogy to Intermediate 22b, starting fromIntermediate 21c

Intermediate 23

A mixture of 5-bromo-4-methyl-3,6 (1H,2H)-pyridazinedione (500 mg, 2.4mmol; Organic & Biomolecular Chemistry 2004, 1782-1788) and phosphorusoxychloride (3 ml) was refluxed for 1 h. The reaction mixture was pouredonto ice water, extracted with dichloromethane, dried over sodiumsulfate and concentrated in vacuum to give the crude product (407 mg,2.1 mmol).

Intermediate 24a

A mixture of the crude intermediate 23 (400 mg, 2.0 mmol),4-tert-butyl-benzylamine (321 μl, 2.0 mmol) andN,N-diisopropylethylamine (348 μl, 2.0 mmol) in 10 ml ethanol was heatedto 70° C. for 48 h. The mixture was cooled to room temperature and thendirectly purified by reversed phase HPLC to give the desired product(230 mg, 525 μmol).

Intermediate 25a

Sodium methylate (30%, 107 μl, 577 μmol) was added to a solution ofintermediate 24a (230 mg, 525 μmol) in 3 ml methanol and heated in themicrowave at 120° C. for 1 h. The crude mixture was directly purified byreversed phase HPLC to give the desired product (154 mg, 355 μmol).

Intermediate 26a

A mixture of intermediate 25a (154 mg, 355 μmol), palladium acetate (8mg, 35 μmol), 1,1′-bis(diphenylphosphino)-ferrocene (20 mg, 35 μmol),sodium acetate (87 mg, 1.1 mmol) in 5 ml methanol and 5 ml DMF wasstirred under a carbon monoxide atmosphere (5 bar) for 48 h at 70° C.The mixture was filtered and concentrated in vacuum. The residue waspurified by reversed phase HPLC to give the corresponding ester (53 mg,154 μmol). A 1 M aqueous solution of sodium hydroxide (386 μl) was addedto a solution of the ester (53 mg, 154 μmol) in 3 ml methanol. Thereaction mixture was stirred for 2 h at room temperature. The reactionmixture was acidified with trifluoroacetic acid and directly purified byreversed phase HPLC to give the desired product (48 mg, 108 μmol).

The following intermediates were synthesized in analogy to intermediates24a, 25a and 26a starting from intermediate 23:

di-Cl- Cl- pyrida- methoxy- zine pyridazine Acid Starting inter- inter-inter- Stereo- amine mediate STRUCTURE mediate STRUCTURE mediateSTRUCTURE chemistry 4 24b

25b

26b

as shown 7- Trifluoro- methyl- 1,2,3,4- tetra- hydro- iso- quinoline 24c

25c

26c

— 17c 24d

25d

26d

relative stereo- chemistry cis 18a 24e

25e

26e

as shown 17b 24f

25f

26f

as shownThe following synthesis sequence allows the preparation of Intermediates17b, 17c, 18a:

Intermediate 27a

To a solution of commercially available 4-(trifluoromethyl)-benzoylchloride (25 g, 112 mmol) in 250 ml dry tetrahydrofurane under nitrogenatmosphere, dimethylamine dihydrochloride (14.7 g, 180 mmol) andpotassium carbonate (49.62 g, 360 mmol) were added at 0° C. The reactionmixture was stirred at room temperature for 18 h. The solvent wasremoved under vacuum, the crude product was dissolved in ethyl acetate.The organic phase was washed with brine, dried over sodium sulfate andconcentrated under vacuum. The crude product was used in the next stepwithout any purification.

Intermediate 28a

Intermediate 27a (25 g) was dissolved in 125 ml of dry tetrahydrofuraneand the reaction mixture was cooled to 0° C. 350 ml of a cooled 0.5 Msolution of (pent-4-enyl)magnesium bromide (Liebigs Annalen der Chemie1982, 1478) was added and the reaction mixture was stirred at roomtemperature for 18 h. The reaction mixture was quenched with a saturatedaqueous ammonium chloride solution. The organic phase was separated,dried over sodium sulfate and concentrated under vacuum. The crudeproduct was purified by flash chromatography to give 25 g of the desiredproduct.

Intermediate 29a

Intermediate 28a was added dropwise to a suspension of (S,S)-teth-TsDpenruthenium chloride (20 mg, 0.032 mmol; Johnson Matthey Catalysts) in 200ml formic acid/triethylamine complex under argon atmosphere.

The reaction mixture was warmed to 70° C. for 18 h. Then, water wasadded and the reaction mixture was extracted with diethyl ether. Theorganic phase was separated, dried over sodium sulfate and concentratedunder vacuum. The crude product (40 g) was used in the next step withoutany purification.

Stereochemistry in analogy to Organic Letters 2000, 1749-51.

The following intermediates were synthesized in analogy to Intermediates27a, 28a and 29a.

synthesis in analogy to intermediate synthesis in analogy synthesis inanalogy 27a to intermediate 28a to intermediate 29a Starting Amide KetonAlcohol Benzoyl Inter- Inter- Inter- Stereo- chloride Source mediateSTRUCTURE mediate STRUCTURE mediate STRUCTURE chemistry 4-methyl-benzoyl chloride Com- mercially available 27b

28b

29b

in analogy to Organic Letters 2000, 1749-51 4- (trifluoro- methoxy)benzoyl chloride Com- mercially available 27c

28c

29c

in analogy to Organic Letters 2000, 1749-51

Intermediate 30a

To a suspension of sodium bicarbonate (40.6 g, 482 mmol) in 600 ml ofacetonitrile, a solution of Intermediate 29a (40 g) in 100 ml ofacetonitrile was added, followed by the addition of iodine (122 g, 482mmol). The reaction mixture was stirred at room temperature for 1 h,then 1000 ml of a saturated aqueous Na₂S₂O₃ solution were added. Themixture was extracted with diethyl ether. Then, the organic phase wasseparated, dried over sodium sulfate and concentrated under vacuum. Thecrude product was purified by flash chromatography to yield 29 g of thedesired cis stereoisomer.

Relative stereochemistry was assigned by ¹H-NMR.

Intermediate 31a

Commercially available phthalimide potassium salt (17.4 g, 94.0 mmol)was added to a solution of Intermediate 30a (29 g, 78.4 mmol) in 250 mlDMF. The reaction mixture was stirred at 90° C. for 18 h. The reactionmixture was concentrated under vacuum, diethyl ether was added and theorganic phase was washed with an aqueous 1 M sodium hydroxide solution.The organic layer was separated, dried over sodium sulfate andconcentrated under vacuum. The crude product (28.7 g) wasre-crystallised using 350 ml of methylcyclohexane. 9.5 g ofenantiomerically enriched product were obtained.

Enantiomerical purity was determined by chiral HPLC (Method 2Ja):

R_(t) (preferred stereoisomer)=6.69 min

R_(t) (second stereoisomer)=6.00 min

Repeated re-crystallisations with methylcyclohexane allowed to increasethe yield of the enantiopure preferred stereoisomer.

The following intermediates were synthesized in analogy to Intermediates30a and 31a.

synthesis in analogy to intermediate 30a synthesis in analogy tointermediate 31a Starting Phtalimide Chiral Inter- Iodo Inter- HPLCmediate Intermediate STRUCTURE mediate STRUCTURE method R_(t) (min) 29b30b

31b

Method 2Ja R_(t) (preferred s stereoisomer) = 6.27 R_(t) (secondstereoisomer) = 5.62 29c 30b

31c

Method 2Ja R_(t) (preferred stereoisomer) = 6.14 R_(t) (secondstereoisomer) = 5.64

Intermediate 17b

Ethanolamine (8.84 ml, 146.4 mmol) was added to a solution ofIntermediate 31a (9.5 g, 24.4 mmol) in 100 ml of toluene. The reactionmixture was stirred at 70° C. for 3 h. Then, the mixture was cooled toroom temperature and diluted with water and ethyl acetate. The organicphase was separated and washed with an aqueous 1M solution of sodiumhydroxide, dried over sodium sulfate and concentrated under vacuum togive the desired product (6.1 g). The crude product was used in the nextstep without any purification.

The following intermediates were synthesized in analogy to Intermediate29a.

Starting Amine Inter- Inter- mediate mediate STRUCTURE 31b 18a

31c 17c

Intermediate 32a

A solution of commercially available 2-(diethoxy-phosphoryl)-propionicacid ethyl ester (100 ml, 462 mmol) in 200 ml THF was added to asuspension of sodium hydride (18.5 g of a 60% suspension on mineral oil,462 mmol) in 800 ml THF at 0° C. and stirred for 1 h. Then, commerciallyavailable dimethoxy-acetaldehyde (142 ml, 554 mmol) was added and themixture was stirred for 30 min at 0° C. The solvent was removed and theresidue was purified by chromatography to give the desired product (36.9g, 196 mmol).

Intermediate 32b

Commercially available 1-triphenylphosphoranylidene-2-propanone (32 g,100 mmol) and methyl pyruvate (15 ml, 150 mmol) were refluxed in 300 mltoluene for 2 days. The solvent was removed and the residue wasdissolved in diisopropylether. The mixture was filtered. The solvent wasremoved in vacuum to give the desired product (15.1 g, 100 mmol).

Intermediate 33a

Intermediate 32a (36.9 g, 196 mmol) was reacted with bromine (11 ml, 215mmol) for six days at room temperature to give the crude product (58.3g, 196 mmol) which was used in the next step without purification.

Intermediate 33b

Was prepared in analogy to intermediate 33a starting from intermediate32b.

Intermediate 34a

Hydrazine hydrate (22.6 ml, 252 mmol) was added to a solution ofintermediate 33a (56.3 g, 190 mmol) in 340 ml acetic acid. The reactionmixture was heated at 150° C. over night. The solvent was removed invacuum and the residue was purified by chromatography to give thedesired product (20.9 g, 111 mmol).

Intermediate 34b

Was prepared in analogy to intermediate 34a starting from intermediate33b.

Intermediate 23a

Intermediate 34a (5.0 g, 22.5 mmol) was added to phosphoryl chloride (5ml) and the reaction mixture was refluxed for 1 h. The reaction mixturewas poured onto ice water and extracted with dichloromethane. Thecombined organic layers were dried over sodium sulfate and concentratedunder vacuum to give the desired product (4.56 g, 22.4 mmol) which wasused in the next step without purification.

Intermediate 23b

Was prepared in analogy to intermediate 23a starting from intermediate34b.

Intermediate 24 g

A mixture of intermediate 23a (53 mg, 325 μmol),4-tert-butyl-benzylamine (53 μl, 325 μmol) and N,N-diisopropylethylamine(240 μl, 1.3 mmol) in 2 ml NMP was heated to 120° C. for 3 h. Themixture was cooled to room temperature and then directly purified byreversed phase HPLC to give the desired product (22 mg, 54 μmol).

Intermediate 24m

A mixture of intermediate 23a (500 mg, 3.1 mmol), commercially available3,4-dichloro-aniline (497 mg, 3.1 mmol) and 1 ml concentratedhydrochloric acid in 8 ml water was heated in a microwave vial to 160°C. for 1 h. The mixture was concentrated under vacuum and then purifiedby reversed phase HPLC to give the desired product (174 mg, 603 μmol).

Intermediate 26 g

A mixture of intermediate 24 g (22 mg, 54 μmol), palladium acetate (1.2mg, 5 μmol), 1,1′-bis(diphenylphosphino)-ferrocene (3 mg, 5 μmol),sodium acetate (13 mg, 163 μmol) in 5 ml methanol and 5 ml DMF wasstirred under a carbon monoxide atmosphere (5 bar) for 48 h at 70° C.The mixture was filtered and concentrated in vacuum. The residue waspurified by reversed phase HPLC to give the corresponding ester (23 mg,54 μmol).

Lithium hydroxide (9 mg, 215 μmol) was added to a solution of the ester(23 mg, 54 μmol) in 2 ml THF and 2 ml water. The reaction mixture wasstirred for 15 min at 100° C. and then concentrated under vacuum. Theresidue was purified by reversed phase HPLC to give the desired product(3 mg, 7 μmol).

The following intermediates were synthesized in analogy to intermediates24 g and 26 g starting from intermediate 23a:

Cl- pyri- Acid Start- dazine inter- Stereo- ing inter- medi- chemis-amine mediate STRUCTURE ate STRUCTURE try 4 24h

26h

as shown 7- Tri- fluoro- methyl- 1,2,3,4- tetra- hydro- iso- quino- line24i

26i

— 17c 24j

26j

relative stereo- chemis- try cis 18a 24k

26k

as shown 17b 24l

26l

as shown Sec speci- fic proto- col 24m

26m

—

The following intermediates were synthesized in analogy to intermediates24 g and 26 g starting from intermediate 23b:

Cl- pyridazine Acid Stereo- Starting amine intermediate STRUCTUREintermediate STRUCTURE chemistry 4-tert-butyl- benzylamine 24n

26n

—

SYNTHESIS OF EXAMPLES

The examples of this invention are synthesized according to thefollowing general synthetic procedures:

Synthetic Procedure:

Examples: 1-23 Example 1

Intermediate 26a (24 mg, 54 μmol), TBTU (22 mg, 68 μmol) andN,N-diisopropylethylamine (76 μl, 433 μmol) were dissolved in 1 ml DMF.Then, intermediate 20a (34 mg, 123 μmol) was added and the reactionmixture was stirred for 2 h. The reaction mixture was diluted withdichloromethane and washed with an aqueous saturated sodium bicarbonatesolution. The organic layer was dried over sodium sulfate andconcentrated in vacuum. The residue was purified by reversed phase HPLCto give the desired product (37 mg, 53 μmol).

HPLC (Method 2 Cc): R_(t). (min)=1.19

[M+H]⁺=587

The following examples were synthesized in analogy to the preparation ofExample 1.

HPLC Ex Inter- [M + R_(t) # STRUCTURE mediate Amine H]⁺ (min) Method 2

26a 20d 526 1.20 2Cc 3

26b 20c 552 1.90 2Ca 4

26c 20c 564 1.99 2Ca 5

26d 20c 638 1.96 2Ca 6

26e 20b 568 1.83 2Ca 7

26f 20c 622 2.012 2Ca 8

26f 20b 622 1.970 2Ca 9

26g 20d 496 1.088 2Cc 10

26h 20c 522 1.785 2Ca 11

26i 20c 534 1.760 2Ca 12

26j 20c 608 1.339 Y1_1 13

26k 20e 526 0.944 Z1_2 14

26j 20e 596 1.200 Y8_1 15

26l 20b 592 1.820 2Ca 16

26l 20c 592 1.828 2Ca 17

26i 20b 534 1.760 2Ca 18

26h 20e 510 0.999 Z1_2 19

26l 20e 580 1.032 Z1_2 20

26i 20e 522 0.957 Z1_2 21

26m 20e 482 0.873 Z1_2 22

26m 20c 494 0.889 Z1_2 23

26n 20d 510 1.340 Y1_1

1. A compound according to formula (I),

wherein A is a group selected from among —NH-L₁-R₇, —NCH₃-L₁-R₇,—O-L₁-R₇, and the structure (II)

wherein L₁ is a linker selected from a bond or a group selected fromamong —C₁-C₂-alkylene, and —C₁-C₂-alkenylene which optionally comprisesone or more groups selected from —O—, —C(O)—, and —NH— in the chain andwhich is optionally substituted by a group selected from among —OH,—NH₂, —C₁-C₃-alkyl, O—C₁-C₆-alkyl, and —CN, wherein R₇ is a ringselected from among —C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl,—C₅-C₁₀-aryl, and —C₅-C₁₀-heteroaryl, wherein the ring R₇ is optionallysubstituted with one or more groups selected from among —CF₃,—C₁-C₆-alkyl, —O—CF₃, —CN, —O—C₁-C₆-alkyl, —C₁-C₆-alkenyl, and—C₁-C₆-alkynyl, and -halogen, or wherein the ring R₇ is optionallysubstituted with one or more groups selected from among —C₅-C₁₀-aryl,—C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl, optionallybeing substituted by one or more groups selected from among —OH, —NH₂,—C₁-C₄-alkyl, —O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, halogen, and ═O, orwherein the ring R₇ is optionally further bi-valently substituted on twoneighbouring ring atoms, such that an annellated ring is formed by oneor more groups selected from among —C₁-C₆-alkylene, —C₂-C₆-alkenyleneand —C₄-C₆-alkynylene, in which one or two carbon centers may optionallybe replaced by 1 or 2 hetero atoms selected from N, O and S, thebivalent group being optionally substituted by one or more groupsselected from —OH, —NH₂, —C₁-C₃-alkyl, —O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃,halogen, and ═O; wherein R₆ is selected from among —H, -halogen, —CN,—O—C₁-C₄-alkyl, —C₁-C₄-alkyl, —CH═CH₂, —C≡CH, —CF₃, —OCF₃, —OCF₂H, and—OCFH₂; wherein R₂ is selected from among —H, -halogen, —CN,—O—C₁-C₄-alkyl, —C₁-C₄-alkyl, —CH═CH₂, —C≡CH, -cyclopropyl, —CF₃, —OCF₃,—OCF₂H, and —OCFH₂; wherein R₃ is selected from among —H, -methyl,-ethyl, -propyl, -1-propyl, -cyclopropyl, —OCH₃, —OH, and —CN; wherein Zis C or N; wherein R₁ is selected from among —H, —C₁-C₄-alkyl, —OH,—O—C₁-C₄-alkyl, -halogen, —CN, —CF₃, and —OCF₃; wherein n is 1, 2 or 3;wherein R₄ and R₅ are independently selected from among an electronpair, —H, and a group selected from among —C₁-C₆-alkyl, —NH₂,—C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl, —C₅-C₁₀-aryl,—C₅-C₁₀-heteroaryl, and —C(O)—N(R₈,R_(8′)), with R₈ and R_(8′)independently being selected from among —H, and —C₁-C₆-alkyl, andwherein R₄ and R₅ if different from an electron pair or —H areoptionally independently substituted with one or more groups selectedfrom among -halogen, —OH, —CF₃, —CN, —C₁-C₆-alkyl, —O—C₁-C₆-alkyl,—O—C₃-C₈-cycloalkyl, —O—C₃-C₈-heterocyclyl, —O—C₅-C₁₀-aryl,—O—C₅-C₁₀-heteroaryl, —C₀-C₆-alkylene-CN, —C₀-C₄-alkylene-O—C₁-C₄-alkyl,—C₀-C₄-alkylene-O—C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-O—C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-O—C₅-C₁₀-aryl,—C₀-C₄-alkylene-O—C₅-C₁₀-heteroaryl,—C₀-C₄-alkylene-Q-C₀-C₄-alkyl-N(R₉,R_(9′)),—C₀-C₄-alkylene-N(R₁₀)-Q-C₁-C₄-alkyl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-N(R₁₀)-Q-C₃-C₈-heterocyclyl,—C₀-C₄-alkylene-N(R₁₀)-Q—C₅-C₁₀-aryl,—C₀-C₄-alkylene-N(R₁₀)-Q—C₅-C₁₀-heteroaryl,—C₀-C₄-alkylene-Q-N(R₁₁,R_(11′)),—C₀-C₄-alkylene-N(R₁₂)-Q-N(R₁₃,R_(13′)), —C₀-C₄-alkylene-R₁₄,—C₀-C₄-alkylene-Q-C₁-C₆-alkyl, —C₀-C₄-alkylene-Q-C₃-C₈-cycloalkyl,—C₀-C₄-alkylene-Q-C₃-C₈-heterocyclyl, —C₀-C₄-alkylene-Q—C₅-C₁₀-aryl,—C₀-C₄-alkylene-Q—C₅-C₁₀-heteroaryl, —C₀-C₄-alkylene-O-Q-N(R₁₅,R_(15′)),and —C₀-C₄-alkylene-N(R₁₆)-Q-O—(R₁₇), wherein Q is selected from among—C(O)—, and —SO₂—, wherein R₁₂, R₁₆, are independently selected fromamong —H, —C₁-C₆-alkyl, and —C₃-C₆-cycloalkyl, wherein R₉, R_(9′), R₁₀,R₁₁, R_(11′), R₁₃, R_(13′), R₁₅, R_(15′), are independently selectedfrom among —H, —C₁-C₆-alkyl, and —C₃-C₆-cycloalkyl, or wherein R₉ andR_(9′), R₁₁ and R_(11′), R₁₃ and R_(13′), R₁₅ and R_(15′) together forma —C₂-C₆-alkylene group, wherein R₁₄ and R₁₇ are independently selectedfrom among —H, —C₁-C₆-alkyl, —C₅-C₁₀-aryl, —C₅-C₁₀-heteroaryl,—C₃-C₈-cycloalkyl, and —C₃-C₈-heterocyclyl, wherein said—C₃-C₈-heterocyclyl optionally comprises nitrogen and/or —SO₂— in thering, and wherein R₁₄ and R₁₇ are optionally substituted with one ormore groups selected from among —OH, —OCH₃, —CF₃, —OCF₃, —CN, -halogen,—C₁-C₄-alkyl, ═O, and —SO₂—C₁-C₄-alkyl, or wherein R₄ and/or R₅ areindependently selected from among an electron pair, —H, and a group ofthe structure -L₂-R₁₈, wherein L₂ is selected from among —NH— and—N(C₁-C₄-alkyl)-, wherein R₁₈ is selected from among —C₅-C₁₀-aryl,—C₅-C₁₀-heteroaryl, —C₃-C₈-cycloalkyl, and —C₃-C₈-heterocyclyl, andwherein R₁₈ is optionally substituted by one or more groups selectedfrom among halogen, —CF₃, —OCF₃, —CN, —OH, —O—C₁-C₄-alkyl, —C₁-C₆-alkyl,—NH—C(O)—C₁-C₆-alkyl, —N(C₁-C₄-alkyl)-C(O)—C₁-C₆-alkyl,—C(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, —NH—S(O)₂—C₁-C₆-alkyl,—N(C₁-C₄-alkyl)-S(O)₂—C₁-C₆-alkyl, and —C(O)—O—C₁-C₆-alkyl, and whereinR₄, R₅ and R₁₈ are optionally further substituted byspiro-C₃-C₈-cycloalkyl or spiro-C₃-C₈-heterocyclyl such that togetherwith R₄, R₅ and/or R₁₈ a spirocycle is formed, wherein saidspiro-C₃-C₈-heterocyclyl optionally comprises one or more groupsselected from among nitrogen, —C(O)—, —SO₂—, and —N(SO₂—C₁-C₄-alkyl)- inthe ring, or wherein R₄, R₅ and R₁₈ are optionally further bi-valentlysubstituted by one or more spirocyclic or annellated ring forming groupsselected from among —C₁-C₆-alkylene, —C₂-C₆-alkenylene, and—C₄-C₆-alkynylene, in which one ore two carbon centers may optionally bereplaced by one or two hetero atoms selected from among N, O and S andwhich may optionally be substituted by one or more groups on one ringatom or on two neighbouring ring atoms selected from among —OH, —NH₂,—C₁-C₃-alkyl, O—C₁-C₆-alkyl, —CN, —CF₃, —OCF₃, and halogen; as well asin form of their acid addition salts with pharmacologically acceptableacids.
 2. The compound of formula (I) according to claim 1, wherein A isa group selected from among —NH-L₁-R₇, —O-L₁-R₇, and the structure (II)

wherein L₁ is a linker selected from a bond or a group selected fromamong —C₁-C₂-alkylene, wherein R₇ is a ring selected from among—C₃-C₈-cycloalkyl, —C₃-C₈-heterocyclyl, and —C₅-C₁₀-aryl, wherein thering R₇ is optionally substituted with one or more groups selected fromamong —CF₃, —C₁-C₆-alkyl, and —O—CF₃, or wherein the ring R₇ isoptionally substituted with one or more groups selected from among—C₅-C₁₀-aryl, optionally being substituted by one or more groupsselected from among —C₁-C₄-alkyl, and —OCF₃; wherein R₆ denotes —CF₃;wherein R₂ is selected from among —H, —C₁-C₄-alkyl, and —CF₃; wherein R₃is selected from among —H, —OCH₃, and —OH; wherein Z denotes C; whereinR₁ denotes —H; wherein n is 2; wherein R₄ denotes —H, and R₅ is a groupselected from —C₃-C₈-heterocyclyl, and wherein R₅ is optionallysubstituted with one or more groups selected from among—C₀-C₄-alkylene-N(R₁₀)-Q-C₁-C₄-alkyl, wherein Q is denotes —SO₂—, andwherein R₁₀, is selected from among —H, and —C₁-C₆-alkyl, or wherein R₄denotes —H, and R₅ is selected from a group of the structure -L₂-R₁₈,wherein L₂ denotes —NH— and wherein R₁₈ is selected from among—C₃-C₈-heterocyclyl, wherein R₁₈ is optionally substituted by one ormore groups selected from among —O—C₁-C₄-alkyl.
 3. The compound offormula (I) according to claim 1, wherein A is —NH-L₁-R₇, and wherein L₁is a bond or wherein L₁ denotes methylene, and wherein R₇ is a ringselected from among -cyclopropyl, -cyclobutyl, -cyclopentyl,-cyclohexyl, -cycloheptyl, -pyrrolidinyl, -piperidinyl, -azepanyl,-tetrahydrofuranyl, -tetrahydropyranyl, -oxepanyl, -phenyl, -pyridyl,and -furanyl, wherein the ring R₇ is optionally substituted with one ormore groups selected from among —F, —Cl, -methyl, -ethyl, -propyl,-i-propyl, -cyclopropyl, -t-butyl, —CF₃, —O—CF₃, —CN, —O-methyl,-furanyl and -phenyl, wherein said -phenyl is optionally independentlysubstituted by one or more groups selected from among —C₁-C₄-alkyl,halogen, —OCH₃, —CF₃, and —OCF₃.
 4. The compound of formula (I)according to claim 1, wherein A is —NH-L₁-R₇ and wherein L₁ is a bond orwherein L₁ denotes methylene, and wherein R₇ is a ring selected fromamong —C₃-C₈-heterocyclyl, and —C₅-C₁₀-aryl, wherein the ring R₇ isoptionally substituted with one or more groups selected from among—O—CF₃— and —C₁-C₆-alkyl, or wherein the ring R₇ is optionallysubstituted with one or more groups selected from -phenyl, optionallybeing substituted by one or more groups selected from —C₁-C₄-alkyl, and—OCF₃.
 5. The compound of formula (I) according to claim 1, wherein Adenotes a group selected from among formula (III)

wherein R₁₉ denotes the ring —C₅-C₁₀-aryl, and wherein the ring R₁₉ isoptionally substituted with one or more groups selected from among—O—CF₃, and —C₁-C₆-alkyl, preferably by a group selected from among—O—CF₃.
 6. The compound of formula (I) according to claim 1, wherein Ais a group selected from among formula (IV) and (V)

wherein R₁₉ is selected from among —H, —O—CF₃, and —C₁-C₆-alkyl.
 7. Thecompound of formula (I) according to claim 1, wherein R₂ is selectedfrom among —H, —CF₃, and —CH₃.
 8. The compound of formula (I) accordingto claim 1, wherein R₃ is selected from among —H, —OCH₃, and -methyl. 9.The compound of formula (I) according to claim 1, wherein R₁ is selectedfrom among-H, and —CH₃.
 10. The compound of formula (I) according toclaim 1, wherein R₄ denotes —H.
 11. The compound of formula (I)according to claim 1, wherein n is
 2. 12. The compound of formula (I)according to claim 1, wherein Z denotes C.
 13. The compound of formula(I) according to claim 1, wherein Z denotes C, and wherein R₄ denotes—H, and wherein R₅ denotes a group of the structure -L₂-R₁₈, wherein L₂is a group selected from among —NH—, and —N(CH₃)—, wherein R₁₈ is—C₆-heterocyclyl comprising 1 hetero atom selected from O, wherein R₁₈is optionally substituted by —O—CH₃; or wherein R₄ denotes —H and R₅denotes a group of the structure —N(R₂₀,R_(20′)), wherein R₂₀ andR_(20′)together form a —C₄-C₅-alkylene group such that a ring is formed,wherein such ring is optionally substituted with one or more groupsselected from among —OH, and —N(C₀-C₁-alkyl)-SO₂—CH₃; or wherein R₄denotes —H, and wherein R₅ denotes a group of the structure —N(R₂₁,R₂₁),wherein R₂₁ and R_(21′)together form a —C₅-alkylene group such that aring is formed, in which one carbon center of the —C₅-alkylene group isreplaced by one hetero atom selected from O.
 14. (canceled)
 15. A methodfor the treatment of inflammatory diseases comprising administering to apatient in need thereof a therapeutic amount of compound according toclaim
 1. 16. The method according to claim 15, wherein the inflammatorydiseases are selected from inflammatory diseases of the respiratorytract.
 17. The method according to claim 16, wherein the diseases areselected from chronic obstructive pulmonary disease, asthma, and cysticfibrosis.
 18. A method for the treatment of neurologic diseasescomprising administering to a patient in need thereof a therapeuticamount of compound according to claim
 1. 19. A method for the treatmentof diabetes mellitus comprising administering to a patient in needthereof a therapeutic amount of compound according to claim
 1. 20. Amethod for the treatment of peripheral atherosclerotic diseasecomprising administering to a patient in need thereof a therapeuticamount of compound according to claim
 1. 21. A method for the treatmentof diabetic nephropathy comprising administering to a patient in needthereof a therapeutic amount of compound according to claim
 1. 22. Themethod of claim 18, wherein the neurologic disease is selected from paindiseases.
 23. The method of claim 22 wherein the pain diseases areselected from inflammatory and neuropathic pain disease.